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BACKGROUND: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. METHODS: Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. RESULTS: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi-targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA-mTOR-AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. CONCLUSION: This real-world data collection illustrates an increasing use of "out-of-trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.
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Antinéoplasiques , Tumeurs , Humains , Enfant , Adulte , Études rétrospectives , Canada , Tumeurs/traitement médicamenteux , Oncologie médicale , Antinéoplasiques/usage thérapeutique , Traitements en cours d'évaluationRÉSUMÉ
BACKGROUND: Hematopoietic stem cell transplantation can be curative for children with difficult-to-treat leukemia. The conditioning regimen utilized is known to influence outcomes. We report outcomes of the conditioning regimen used at the Alberta Children's Hospital, consisting of busulfan (with pharmacokinetic target of 3750 µmol*min/L/day ±10%) for 4 days, higher dose (250 mg/m2 ) fludarabine and 400 centigray (cGy) of total body irradiation. PROCEDURE: This retrospective study involved children receiving transplant for acute lymphoblastic leukemia (ALL). It compared children who fell within the target range for busulfan with those who were either not measured or were measured and fell outside this range. All other treatment factors were identical. RESULTS: Twenty-nine children (17 within target) were evaluated. All subjects engrafted neutrophils with a median [interquartile range] time of 14 days [8-30 days]. The cumulative incidence of acute graft-versus-host disease was 44.8% [95% confidence interval, CI: 35.6%-54.0%], while chronic graft-versus-host disease was noted in 16.0% [95% CI: 8.7%-23.3%]. At 2 years, the overall survival was 78.1% [95% CI: 70.8%-86.4%] and event-free survival was 74.7% [95% CI: 66.4%-83.0%]. Cumulative incidence of relapse was 11.3% [95% CI: 5.1%-17.5%]. There were no statistically significant differences in between the group that received targeted busulfan compared with the untargeted group. CONCLUSION: Our conditioning regiment for children with ALL resulted in outcomes comparable to standard treatment with acceptable toxicities and significant reduction in radiation dose. Targeting busulfan dose in this cohort did not result in improved outcomes.
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Maladie du greffon contre l'hôte , Transplantation de cellules souches hématopoïétiques , Leucémie aigüe myéloïde , Leucémie-lymphome lymphoblastique à précurseurs B et T , Vidarabine/analogues et dérivés , Enfant , Humains , Busulfan/usage thérapeutique , Irradiation corporelle totale/effets indésirables , Études rétrospectives , Transplantation de cellules souches hématopoïétiques/effets indésirables , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Vidarabine/usage thérapeutique , Maladie du greffon contre l'hôte/traitement médicamenteux , Conditionnement pour greffe/méthodes , Leucémie aigüe myéloïde/traitement médicamenteuxRÉSUMÉ
PURPOSE: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome. METHODS: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4). RESULTS: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001). CONCLUSION: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity.
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Fractures osseuses , Fractures ostéoporotiques , Fractures du rachis , Enfant , Humains , Glucocorticoïdes/effets indésirables , Corps vertébral , Densité osseuse , Fractures osseuses/induit chimiquement , Fractures du rachis/étiologie , Fractures du rachis/induit chimiquement , Fractures ostéoporotiques/induit chimiquementRÉSUMÉ
OBJECTIVES: The primary objective was to determine if individualised yoga for hospitalised children receiving intensive chemotherapy was associated with less fatigue using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL MFS) compared with iPad control. METHODS: This was a multicentre randomised controlled trial of individualised yoga in paediatric patients aged 8-18 years who were inpatients receiving intensive chemotherapy for leukaemia, lymphoma or haematopoietic cell transplantation. Participants were randomised to yoga or iPad groups; allocated programme was delivered individually by trained yoga instructors 5 days/week for 21 days. The primary outcome was day 21 guardian-reported general fatigue using the PedsQL MFS. Secondary outcomes included day 21 PedsQL sleep/rest and cognitive fatigue, Fatigue Scale and PedsQL Acute Cancer Module, and systemic opioid administration. RESULTS: The study was closed early for poor accrual when 125/210 planned participants had been enrolled and randomised to yoga (n=62) or iPad (n=63). Guardian-reported PedsQL MFS general fatigue scores on day 21 were not significantly different between groups (adjusted difference 7.2, 95% CI -2.6 to 16.9) in favour of yoga. However, day 21 cognitive fatigue (adjusted difference 9.0, 95% CI 0.9 to 17.1), cognitive problems (adjusted difference 11.2, 95% CI 3.5 to 19.0) and communication (adjusted difference 10.6, 95% CI 0.8 to 20.4) were significantly better in the yoga compared with the iPad group. There were no significant differences in the other secondary outcomes including PedsQL sleep/rest fatigue (adjusted difference 4.9, 95% CI -3.5 to 13.3). CONCLUSIONS: The effect of individualised yoga on general fatigue is uncertain in paediatric patients receiving intensive chemotherapy. However, yoga significantly improved cognitive fatigue and cognitive problems. TRIAL REGISTRATION NUMBER: NCT02134782.
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Fraser Syndrome is a rare, multisystemic autosomal recessive disorder characterized by disrupted epithelial-mesenchymal associations upon loss of Fraser Complex genes. Disease manifestation and affected organs are highly variable. Digit malformations such as syndactyly are common but of unclear developmental origins. We explored if zebrafish fraser extracellular matrix complex subunit 1 (fras1) mutants model Fraser Syndrome-associated appendicular skeleton patterning defects. Approximately 10% of fras1 mutants survive to adulthood, displaying striking and varied fin abnormalities, including endochondral bone fusions, ectopic cartilage, and disrupted caudal fin symmetry. The fins of surviving fras1 mutants frequently have fewer and unbranched bony rays. fras1 mutant fins regenerate to their original size but with exacerbated ray branching and fin symmetry defects. Single cell RNA-Seq analysis, in situ hybridizations, and antibody staining show specific Fraser complex expression in the basal epidermis during regenerative outgrowth. Fras1 and Fraser Complex component Frem2 accumulate along the basal side of distal-most basal epidermal cells. Greatly reduced and mislocalized Frem2 accompanies loss of Fras1 in fras1 mutants. The Sonic hedgehog signaling between distal basal epidermis and adjacent mesenchymal pre-osteoblasts that promotes ray branching persists upon Fraser Complex loss. However, fras1 mutant regenerating fins exhibit extensive sub-epidermal blistering associated with a disorganized basal epidermis and adjacent pre-osteoblasts. We propose Fraser Complex-supported tissue layer adhesion enables robust integrated tissue morphogenesis involving the basal epidermis and osteoblasts. Further, we establish zebrafish fin development and regeneration as an accessible model to explore mechanisms of Fraser Syndrome-associated digit defects and Fraser Complex function at epithelial-mesenchymal interfaces.
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Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD Z-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (-1.09 ± 1.53 versus -1.27 ± 1.25, p = 0.549). LS BMD Z-scores declined from baseline to 12 months in children with ON (-0.31 ± 1.02) but not in those without (0.13 ± 0.82, p = 0.035); the hip BMD Z-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (-1.77 ± 1.22) compared to those without (-1.03 ± 1.07, p = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD Z-scores were lower in children with ON (hip -0.98 ± 0.95 versus -0.28 ± 1.06, p = 0.010; TB -1.36 ± 1.10 versus -0.48 ± 1.50, p = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, p = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15-2.13; p = 0.004), and hip BMD Z-score at MRI (OR 2.23; 95% CI, 1.02-4.87; p = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD Z-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD Z-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Leucémies , Ostéonécrose , Ostéoporose , Humains , Enfant , Densité osseuse , Vertèbres lombales , Ostéonécrose/induit chimiquement , Ostéonécrose/imagerie diagnostique , Absorptiométrie photonique/méthodesRÉSUMÉ
Zebrafish robustly regenerate fins, including their characteristic bony ray skeleton. Amputation activates intra-ray fibroblasts and dedifferentiates osteoblasts that migrate under a wound epidermis to establish an organized blastema. Coordinated proliferation and re-differentiation across lineages then sustains progressive outgrowth. We generate a single cell transcriptome dataset to characterize regenerative outgrowth and explore coordinated cell behaviors. We computationally identify sub-clusters representing most regenerative fin cell lineages, and define markers of osteoblasts, intra- and inter-ray fibroblasts and growth-promoting distal blastema cells. A pseudotemporal trajectory and in vivo photoconvertible lineage tracing indicate distal blastemal mesenchyme restores both intra- and inter-ray fibroblasts. Gene expression profiles across this trajectory suggest elevated protein production in the blastemal mesenchyme state. O-propargyl-puromycin incorporation and small molecule inhibition identify insulin growth factor receptor (IGFR)/mechanistic target of rapamycin kinase (mTOR)-dependent elevated bulk translation in blastemal mesenchyme and differentiating osteoblasts. We test candidate cooperating differentiation factors identified from the osteoblast trajectory, finding IGFR/mTOR signaling expedites glucocorticoid-promoted osteoblast differentiation in vitro. Concordantly, mTOR inhibition slows but does not prevent fin regenerative outgrowth in vivo. IGFR/mTOR may elevate translation in both fibroblast- and osteoblast-lineage cells during the outgrowth phase as a tempo-coordinating rheostat.
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Transduction du signal , Danio zébré , Animaux , Danio zébré/métabolisme , Différenciation cellulaire , Protéines de poisson-zèbre/génétique , Protéines de poisson-zèbre/métabolisme , Sérine-thréonine kinases TOR/génétique , Sérine-thréonine kinases TOR/métabolisme , Récepteurs des somatomédines/métabolisme , Nageoires animales/métabolismeRÉSUMÉ
INTRODUCTION: Intravenous hydration may be utilized to prevent nephrotoxicity and facilitate drug elimination in patients receiving high-dose chemotherapy. Prolonged hydration protocols may lead to delayed initiation and completion of therapy, lengthening hospital admissions. Rapid hydration protocols have been implemented to reduce the time required for patients to meet parameters for chemotherapy administration. This study aims to evaluate a rapid hydration protocol implemented at the Alberta Children's Hospital (ACH). METHODS: Starting January 2018 through May 2018, data was prospectively collected for pediatric oncology acute care and ambulatory patients at ACH receiving methotrexate (MTX), cisplatin, cyclophosphamide, or ifosfamide. The primary outcome was the time to achieve pre-determined urine parameters prior to chemotherapy administration. Secondary outcomes included the proportion of cycles that achieved urine parameters and the efficacy of each rapid hydration step. RESULTS: A total of 22 cycles were included, 13 for MTX and 9 for non-MTX chemotherapy. Median time to meet all urine parameters was 120â min (range 30-600â min). Two cycles (15%) failed rapid hydration in the MTX group, while no cycles required further hydration in the non-MTX group. Adverse events potentially attributable to hydration were mild and did not require intervention. CONCLUSION: The ACH rapid hydration protocol resulted in reduced time to meet target urine parameters. The results of this quality assurance review support the continued use of rapid hydration prior to chemotherapy administration.
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Ifosfamide , Méthotrexate , Enfant , Humains , Cisplatine/effets indésirables , Cyclophosphamide , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutiqueRÉSUMÉ
The National Institutes of Health Consensus criteria for chronic graft-versus-host disease (cGVHD) diagnosis can be challenging to apply in children, making pediatric cGVHD diagnosis difficult. We aimed to identify diagnostic pediatric cGVHD biomarkers that would complement the current clinical criteria and help differentiate cGVHD from non-cGVHD. The Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study, open at 27 transplant centers, prospectively evaluated 302 pediatric patients after hematopoietic cell transplant (234 evaluable). Forty-four patients developed cGVHD. Mixed and fixed effect regression analyses were performed on diagnostic cGVHD onset blood samples for cellular and plasma biomarkers, with individual markers declared relevant if they met 3 criteria: an effect ratio ≥1.3 or ≤0.75; an area under the curve (AUC) of ≥0.60; and a P value <5.814 × 10-4 (Bonferroni correction) (mixed effect) or <.05 (fixed effect). To address the complexity of cGVHD diagnosis in children, we built a machine learning-based classifier that combined multiple cellular and plasma biomarkers with clinical factors. Decreases in regulatory natural killer cells, naïve CD4 T helper cells, and naïve regulatory T cells, and elevated levels of CXCL9, CXCL10, CXCL11, ST2, ICAM-1, and soluble CD13 (sCD13) characterize the onset of cGVHD. Evaluation of the time dependence revealed that sCD13, ST2, and ICAM-1 levels varied with the timing of cGVHD onset. The cGVHD diagnostic classifier achieved an AUC of 0.89, with a positive predictive value of 82% and a negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. This trial was registered at www.clinicaltrials.gov as #NCT02067832.
Sujet(s)
Syndrome de bronchiolite oblitérante , Maladie du greffon contre l'hôte , Transplantation de cellules souches hématopoïétiques , Humains , Enfant , Transplantation de cellules souches hématopoïétiques/effets indésirables , Molécule-1 d'adhérence intercellulaire , Protéine-1 analogue au récepteur de l'interleukin-1 , Maladie du greffon contre l'hôte/diagnostic , Maladie du greffon contre l'hôte/étiologie , Marqueurs biologiquesRÉSUMÉ
BACKGROUND/OBJECTIVES: Despite advances in the treatment of sickle cell disease (SCD), cerebrovascular and cognitive insults can have lifelong consequences. Hematopoietic cell transplantation (HCT) is an established curative therapy, and recent studies have demonstrated efficacy with reduced toxicity nonmyeloablative (NMA) regimens, but little is known about neuropsychological outcomes. The objective of this study was to describe neuropsychological, behavioral, and quality-of-life outcomes with medical correlates in children with SCD who received an NMA matched sibling donor (MSD) HCT. DESIGN/METHODS: Retrospective cohort analysis of nine recipients with hemoglobin SS SCD who underwent MSD HCT using the National Institutes of Health (NIH) NMA protocol. RESULTS: Mean full-scale intellectual functioning (FSIQ) was average pre-HCT (FSIQ = 92.1, SD 9.0; n = 8) and 2 years post-HCT (mean FSIQ = 96.6; SD 11.1; N = 9). Neuropsychological functioning was largely average across all cognitive domains, and no pre/post-HCT differences were found to be statistically significant given the small sample size. However, effect sizes revealed moderate improvements in processing speed (Cohen's d = .72) and verbal memory (Cohen's d = .60) post-HCT, and declines in measures of attention (Cohen's d = -.54) and fine motor speed and dexterity (Cohen's d = -.94). Parents endorsed better quality of life (Cohen's d = .91), less impact of SCD on their family, and less worry about their child's future (Cohen's d = 1.44). CONCLUSION: Neuropsychological functioning in a sample of children and adolescents treated uniformly with NMA MSD HCT remained stable or improved in most cognitive domains, and improvements in quality of life and family functioning were observed.
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Drépanocytose , Transplantation de cellules souches hématopoïétiques , Adolescent , Drépanocytose/thérapie , Enfant , Transplantation de cellules souches hématopoïétiques/méthodes , Humains , Qualité de vie , Études rétrospectives , Fratrie , Résultat thérapeutiqueRÉSUMÉ
Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7-45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.
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Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.
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Maladie du greffon contre l'hôte/métabolisme , Acides cétoglutariques/métabolisme , Adolescent , Marqueurs biologiques/sang , Marqueurs biologiques/métabolisme , Enfant , Enfant d'âge préscolaire , Maladie chronique , Femelle , Maladie du greffon contre l'hôte/sang , Transplantation de cellules souches hématopoïétiques/effets indésirables , Humains , Nourrisson , Acides cétoglutariques/sang , Mâle , Métabolome , Appréciation des risquesRÉSUMÉ
BACKGROUND: Postoperative pain management following donor nephrectomy can prove challenging for immediate discharge on postoperative day 1 or 2. Although the standard for pain control is utilization of opioids, this increases the risk of postoperative ileus and, if continued inappropriately, increases excess opioids circulating in the community. One strategy that proposes to limit postoperative opioids in kidney donors is the continuous infusion of local anesthetics (CILA), though the effect on patient outcomes is unclear. OBJECTIVE: The purpose of this study was to evaluate the effectiveness of postoperative CILA to decrease opioid usage in kidney donors who undergo laparoscopic nephrectomy. METHODS: A retrospective analysis was conducted of kidney donors who underwent laparoscopic nephrectomy and received CILA (CILA group) compared with kidney donors who received standard-of-care (SOC) postoperative analgesia. The primary outcome was the mean total oral morphine equivalents (OMEs) administered following surgery. RESULTS: A total of 176 kidney donors were evaluated, 88 in each group. The mean OME administered in the CILA group was significantly higher than in the SOC group: 194.8 versus 133.5 mg (P = 0.003). Mean total postoperative administration of acetaminophen was also increased in the CILA group: 3736.9 versus 2611.6 mg (P = 0.0041). Mean length of stay following surgery was higher in the kidney donors who received CILA, whereas return to bowel function, time to ambulation, and pain scores were not significantly different. CONCLUSION AND RELEVANCE: This report demonstrated that CILA is not an effective modality to reduce opioid utilization or improve recovery in kidney donors following laparoscopic nephrectomy.
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Analgésiques morphiniques , Anesthésiques locaux , Bupivacaïne , Cathéters , Humains , Rein , Néphrectomie , Douleur postopératoire/traitement médicamenteux , Douleur postopératoire/prévention et contrôle , Études rétrospectivesRÉSUMÉ
There is experimental and clinical data to indicate the contribution of immune-escape mechanisms in relapsed/refractory pediatric leukemia. Studies have shown the accumulation of mutations that translate to peptides containing tumor-specific epitopes (neoantigens). The effectiveness of neoantigen-based vaccines has been shown in several clinical trials in adults. Though the initial results are encouraging, this knowledge must be developed to account for the uniqueness of pediatric cancer biology. We have completed the initial proof-of-concept analysis on a high-risk pediatric leukemia specimen and identified usable neoantigen sequences. We describe this approach, including the bioinformatics method and experimental model to verify their function that can be further broadened for personalized neoantigen prediction and testing for the generation of anticancer vaccines against high-risk pediatric leukemias.
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Vaccins anticancéreux , Leucémies , Tumeurs , Adulte , Antigènes néoplasiques , Enfant , Humains , Immunothérapie/méthodes , Leucémies/thérapieRÉSUMÉ
Animal pigment patterns play important roles in behavior and, in many species, red coloration serves as an honest signal of individual quality in mate choice. Among Danio fishes, some species develop erythrophores, pigment cells that contain red ketocarotenoids, whereas other species, like zebrafish (D. rerio) only have yellow xanthophores. Here, we use pearl danio (D. albolineatus) to assess the developmental origin of erythrophores and their mechanisms of differentiation. We show that erythrophores in the fin of D. albolineatus share a common progenitor with xanthophores and maintain plasticity in cell fate even after differentiation. We further identify the predominant ketocarotenoids that confer red coloration to erythrophores and use reverse genetics to pinpoint genes required for the differentiation and maintenance of these cells. Our analyses are a first step toward defining the mechanisms underlying the development of erythrophore-mediated red coloration in Danio and reveal striking parallels with the mechanism of red coloration in birds.
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Mélanophores/physiologie , Pigmentation/génétique , Danio zébré/croissance et développement , Animaux , Différenciation cellulaire , Phénotype , Phylogenèse , Pigments biologiques , Spécificité d'espèce , Danio zébré/génétiqueRÉSUMÉ
Molecular and cellular mechanisms underlying variation in adult form remain largely unknown. Adult pigment patterns of fishes in the genus Danio, which includes zebrafish, Danio rerio, consist of horizontal stripes, vertical bars, spots and uniform patterns, and provide an outstanding opportunity to identify causes of species level variation in a neural crest derived trait. Understanding pigment pattern variation requires quantitative approaches to assess phenotypes, yet such methods have been mostly lacking for pigment patterns. We introduce metrics derived from information theory that describe patterns and pattern variation in Danio fishes. We find that these metrics used singly and in multivariate combinations are suitable for distinguishing general pattern types, and can reveal even subtle phenotypic differences attributable to mutations. Our study provides new tools for analyzing pigment pattern in Danio and potentially other groups, and sets the stage for future analyses of pattern morphospace and its mechanistic underpinnings.
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Développement embryonnaire/génétique , Métamorphose biologique/génétique , Crête neurale/embryologie , Pigmentation/génétique , Danio zébré/embryologie , Animaux , Évolution biologique , Embryon non mammalien , Mutation , PhénotypeRÉSUMÉ
Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione-s-transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model-based, first-dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu-based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age-dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first-dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, -0.5%; 95% confidence interval [CI], -3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%-20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.
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Busulfan/administration et posologie , Glutathione transferase/génétique , Transplantation de cellules souches hématopoïétiques/méthodes , Modèles biologiques , Administration par voie intraveineuse , Adolescent , Antinéoplasiques alcoylants/administration et posologie , Antinéoplasiques alcoylants/pharmacocinétique , Aire sous la courbe , Busulfan/pharmacocinétique , Enfant , Enfant d'âge préscolaire , Relation dose-effet des médicaments , Femelle , Humains , Nourrisson , Mâle , Polymorphisme génétique , Médecine de précision , Conditionnement pour greffe , Vidarabine/administration et posologie , Vidarabine/analogues et dérivés , Jeune adulteRÉSUMÉ
The most frequent complication of allogeneic hematopoietic stem cell transplantation is acute Graft versus Host Disease (aGVHD). Proliferation and differentiation of donor T cells initiate inflammatory response affecting the skin, liver, and gastrointestinal tract. Besides recipient-donor HLA disparities, disease type, and the conditioning regimen, variability in the non-HLA genotype have an impact on aGVHD onset, and genetic variability of key cytokines and chemokines was associated with increased risk of aGVHD. To get further insight into the recipient genetic component of aGVHD grades 2-4 in pediatric patients, we performed an exome-wide association study in a discovery cohort (n = 87). Nine loci sustained correction for multiple testing and were analyzed in a validation group (n = 168). Significant associations were replicated for ERC1 rs1046473, PLEK rs3816281, NOP9 rs2332320 and SPRED1 rs11634702 variants through the interaction with non-genetic factors. The ERC1 variant was significant among patients that received the transplant from HLA-matched related individuals (p = 0.03), bone marrow stem cells recipients (p = 0.007), and serotherapy-negative patients (p = 0.004). NOP9, PLEK, and SPRED1 effects were modulated by stem cell source, and serotherapy (p < 0.05). Furthermore, ERC1 and PLEK SNPs correlated with aGVHD 3-4 independently of non-genetic covariates (p = 0.02 and p = 0.003). This study provides additional insight into the genetic component of moderate to severe aGVHD.
Sujet(s)
Maladie du greffon contre l'hôte , Transplantation de cellules souches hématopoïétiques , Maladie aigüe , Enfant , Prédisposition génétique à une maladie/étiologie , Maladie du greffon contre l'hôte/génétique , Transplantation de cellules souches hématopoïétiques/effets indésirables , Humains , Donneurs de tissus , Conditionnement pour greffe/effets indésirablesRÉSUMÉ
BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections can have serious consequences during the period of aplasia and lymphopenia following hematopoietic stem cell transplantation (HSCT). Large pediatric cohort studies examining the effect of antiviral prophylaxis against these viruses are scarce. The present study aimed to analyse the potential effect of antiviral prophylaxis (acyclovir and famciclovir) on active post-transplant EBV and CMV infection in a pediatric cohort of allogeneic HSCT recipients. METHODS: We used data from the TREASuRE cohort, consisting of 156 patients who had a first allogeneic HSCT, enrolled in four pediatric centers in Canada between July 2013 and March 2017. Follow-up was performed from the time of transplant up to 100 days post-transplant. Adjusted hazard ratio (HR) with 95% confidence intervals (CI) for the association between antiviral prophylaxis with acyclovir and/or famciclovir and EBV and CMV DNAemia was estimated using multivariate Cox regression models. RESULTS: The post-transplant cumulative incidence of EBV and CMV DNAemia at 100 days of follow-up were, respectively, 34.5% (95% CI: 27.6-42.6) and 19.9% (95% CI: 14.5-27.1). For acyclovir, the adjusted hazard ratio (HR) for CMV and EBV DNAemia was 0.55 (95% CI: 0.24-1.26) and 1.41 (95% CI: 0.63-3.14), respectively. For famciclovir, the adjusted HR were 0.82 (95% CI: 0.30-2.29) and 0.79 (95% CI: 0.36-1.72) for CMV and EBV DNAemia, respectively. CONCLUSION: The antivirals famciclovir and acyclovir did not reduce the risk of post-transplant CMV and EBV DNAemia among HSCT recipients in our pediatric population.
RÉSUMÉ
BACKGROUND: Epstein-Barr virus (EBV) can cause severe disease following hematopoietic stem cell transplant (HSCT), including post-transplant lymphoproliferative disorder (PTLD). The objective was to analyze risk factors associated with post-transplant EBV outcomes among pediatric allogeneic HSCT recipients. METHODS: We used data from 156 pediatric allogeneic HSCT recipients enrolled in the Canadian multicenter TREASuRE study. Cox and Prentice-Williams-Petersen models were used to analyze risk factors for post-transplant EBV events including occurrence and recurrence of EBV DNAemia, increase in EBV viral load (EBV-VL), and preemptive use of rituximab, an effective therapy against PTLD. RESULTS: Females were at higher risk for increasing EBV-VL (adjusted hazard ratio (HR) = 2.83 [95% confidence intervals (CI): 1.33-6.03]) and rituximab use (HR = 3.08 [1.14-8.30]), but had the same EBV DNAemia occurrence (HR = 1.21 [0.74-1.99]) and recurrence risks (HR=1.05 [0.70-1.58]) compared to males. EBV DNAemia was associated with recipient pre-transplant EBV seropositivity (HR = 2.47 [1.17-5.21]) and with graft from an EBV-positive donor (HR = 3.53 [1.95-6.38]). Anti-thymocyte globulin (ATG) was strongly associated with all EBV outcomes, including the use of rituximab (HR = 5.33 [1.47-19.40]). Mycophenolate mofetil (MMF) significantly decreased the risk of all EBV events including the rituximab use (HR = 0.13 [0.03-0.63]). CONCLUSION: This study in pediatric allogeneic HSCT patients reveals a reduced risk of all EBV outcomes with the use of MMF. Risk factors for EBV events such as EBV-VL occurrence and recurrence include EBV positivity in the donor and recipient, and use of ATG, whereas risk factors for the most severe forms of EBV outcome (EBV-VL and the use of rituximab) include female sex and ATG use.