Managing therapy-associated neurotoxicity in children with ALL.
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ABSTRACT:
SUBMITTER: Bhojwani D
PROVIDER: S-EPMC8791096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The pathophysiological etiologies related with the development of Autism Spectrum Disorders (ASD) remain controversial. Different authors have studied neurotoxins such as mercury (Hg) and their relationship with ADS. The objective of this study was to assess the levels of Hg in hair in a group of ASD children (chronic exposure) and in urinary excretion (acute exposure), in comparison to a healthy group. METHODS:A case-control study was conducted in Spanish children. We compared 54 ASD children (aged 2-6) with no other associated pathology to a normally-developing control group (54 subjects). RESULTS:There were no differences in urine (p:0.631) and hair (p:1.000) samples percentages below the limits of detection between the control and the ASD groups, and also between patients in the regression ASD subgroup (AMR) (p:0.08) and the non-regression ASD subgroup (ANMR) (p:0.705). When the analysis was adjusted for age and sex, the differences between Hg levels maintained not significant. There were no correlations between Hg concentrations in the ASD group as a whole (p: 0.739), or when they were subdivided into ASD-AMR (p: 0.739) and ASD-ANMR (p: 0.363). CONCLUSIONS:The present study shows no evidence in our geographical area to support an association between mercury neurotoxicity and the etiopathogenesis of ASD.
| S-EPMC7017444 | biostudies-literature
Project description:IntroductionTreatment with CD19 chimeric antigen receptor (CAR) T cells is an innovative therapeutic approach for patients with relapsed/refractory diffuse large B cell lymphoma (r/rDLBCL) and B-lineage acute lymphoblastic leukemia (r/rALL). However, convincing therapeutic response rates can be accompanied by cytokine release syndrome (CRS) and severe neurotoxicity termed immune effector cell-associated neurotoxicity syndrome (ICANS).MethodsSingle center, prospective observational study of fifteen consecutive r/r DLBCL patients treated with Tisagenlecleucel within 1 year at Hannover Medical School. Extensive neurological work-up prior to CAR T cell infusion included clinical examination, cognitive testing (Montreal-Cognitive-Assessment), brain MRI, electroencephalogram, electroneurography, and analysis of cerebrospinal fluid. After CAR T cell infusion, patients were neurologically examined for 10 consecutive days. Afterwards, all patients were assessed at least once a week.ResultsICANS occurred in 4/15 patients (27%) within 6 days (4-6 days) after CAR T cell infusion. Patients with ICANS grade 2 (n = 3) exhibited similar neurological symptoms including apraxia, expressive aphasia, disorientation, and hallucinations, while brain MRI was inconspicuous in either case. Treatment with dexamethasone rapidly resolved the clinical symptoms in all three patients. Regarding baseline parameters prior to CAR T cell treatment, patients with and without ICANS did not differ.ConclusionsIn our cohort, ICANS occurred in only every fourth patient and rather low grade neurotoxicity was found during daily examination. Our results demonstrate that a structured neurological baseline examination and close monitoring are helpful to detect CAR T cell related neurotoxicity already at an early stage and to potentially prevent higher grade neurotoxicity.
| S-EPMC8744256 | biostudies-literature
Project description:Neurotoxicity associated with CAR-T cell therapy can be life-threatening. With rapid development of CAR-T therapies, a systematic method is needed to identify and monitor symptoms of neurotoxicity, elucidate potential etiologies, and compare toxicity across trials. This paper presents a systematic evaluation developed and used to prospectively assess neurotoxicity in our phase I anti-CD22 CAR-T-cell trial and describes the symptoms of neurotoxicity identified using this methodology. Central nervous system (CNS) studies included routine lumbar punctures performed for disease evaluation pretherapy and posttherapy and a baseline brain MRI. Brief cognitive evaluations, assessing 4 domains (attention, working memory, cognitive flexibility, and processing speed), were administered preinfusion and postinfusion. A newly developed CAR-T-specific neurological symptom checklist (NSC) was completed by caregivers at 3 designated time-points. Serial serum cytokine levels were compared with neurotoxicity symptoms and severity. The majority of the first 22 consecutively treated subjects (ages, 7-30) demonstrated stable or improved cognitive test scores following therapy and no irreversible neurotoxicity, despite CAR-T-related antileukemic response, cytokine release syndrome, and trafficking of CAR-T cells to the CSF. The NSC allowed us to document the type and timing of symptoms and explore the etiology of neurotoxicity associated with CD22 CAR-T therapy. Cytokine profiling demonstrated that more concerning symptoms of neurotoxicity, such as hallucination and disorientation, were significantly associated with higher serum cytokine levels, supporting the hypothesis of inflammation-driven neurotoxicity. Systematic assessments of neurotoxicity were feasible in acutely ill children and young adults and served to characterize and monitor the symptoms associated with CAR-T therapy. We recommend these evaluations be incorporated into future immunotherapy protocols.
| S-EPMC6086728 | biostudies-literature
Project description:Little is known about the psychosocial profiles of parents who have a child with an undiagnosed chronic illness. The National Institutes of Health Undiagnosed Diseases Network (UDN) evaluates individuals with intractable medical findings, with the objective of discovering the underlying diagnosis. We report on the psychosocial profiles of 50 parents whose children were accepted to one of the network's clinical sites. Parents completed questionnaires assessing anxiety, depression, coping self-efficacy, and health care empowerment at the beginning of their child's UDN clinical evaluation. Parents of undiagnosed children had high rates of anxiety and depression (~?40%), which were significantly inversely correlated with coping self-efficacy, but not with health care empowerment. Coping self-efficacy, depressive, and anxiety symptoms were better in parents with older children and with longer duration of illness. Gender differences were identified, with mothers reporting greater health care engagement than fathers. Overall, our findings suggest that parents of children with undiagnosed diseases maintain positive coping self-efficacy and remain actively engaged in health care and to a lesser degree tolerance for uncertainty, but these come with a high emotional cost to the parents. As the parents' psychological needs may not be obvious, these should be ascertained and the requisite support provided.
| S-EPMC6028305 | biostudies-literature
Project description:Food selectivity is common in children with autism spectrum disorder (ASD). It can be defined as the unwillingness to eat common or new foods, resulting in a lack of variety in the diet or limited food consumption for multiple reasons, such as inflexibility or sensory alterations. We conducted a peer scoping review to describe the interventions that are carried out from occupational therapy (OT) in children with ASD with food selectivity. Two authors independently searched the databases PubMed, Scopus, Web of Science, and EMBASE, as well as the OT journals indexed in Journal Citation Reports. Articles exploring OT interventions in children (≤12 years) with ASD and food selectivity, published in Spanish or English, with experimental design, and with full text available were included. Of the 1445 articles identified, 8 articles met the inclusion criteria. Three main intervention categories were identified: sensory-behavioral, family focused, and other interventions. Most of the interventions from OT were aimed at treating sensory-behavioral aspects. Only three articles described interventions led exclusively by occupational therapists, and the rest were led by a multidisciplinary team. Finally, although these interventions are not exclusive to OT, occupational therapists can participate together with other professionals as an essential component in the treatment of food selectivity in children with ASD.
| S-EPMC8620957 | biostudies-literature
Project description:Although corticosteroids remain a mainstay of therapy for UC, a meta-regression of cohort studies in acute severe ulcerative colitis (UC) showed that 29% of patients fail corticosteroid therapy and require escalation of medical management or colectomy. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response. 20 corticosteroid responsive (PUCAI < 35 by day 5) and 20 corticosteroid resistant patients (PUCAI ≥ 35 by day 5 and need for 2nd line medical therapy or colectomy by hospital discharge) were selected from a prospectively accrued cohort of patients hospitalized for intravenous corticosteroid treatment of severe UC. Total RNA was extracted from blood samples collected on day 3 of intravenous corticosteroid therapy. The eluted transcriptomes were quantified on Affymetrix Human Gene 1.0 ST arrays. The data was analysed by the local-pooled error method for discovery of differential gene expression and false discovery rate correction was applied to adjust for multiple comparisons. P-values less than 0.05 after correction were considered significant.
2010-08-31 | E-GEOD-21231 | biostudies-arrayexpress
Project description:Metronidazole is a commonly used antimicrobial worldwide. The most common side effects that have been reported are nausea, vomiting and hypersensitivity reactions. However, neurotoxicity has been reported with the use of metronidazole but rather rare. The most common neurological manifestation is peripheral neuropathy involvement in the form of sensory loss. It is worth mentioning that central neurotoxicity is a rare side effect of metronidazole use but reversible. The manifestations vary from a headache, altered mental status to focal neurological deficits. The diagnosis is mainly by neuroimaging in the setting of acute neurological change in the patient status. Here, we report a case of metronidazole-induced neurotoxicity in a 38-year-old male patient who was admitted with a brain abscess and was started on metronidazole for more than 10 weeks.
| S-EPMC5911128 | biostudies-literature
Project description:BACKGROUND:Exposure to triclosan, an endocrine disrupting chemical, may affect thyroid hormone homeostasis and adversely affect neurodevelopment. OBJECTIVE:Using a longitudinal pregnancy and birth cohort, we investigated associations between triclosan exposures during different time windows, and cognitive test scores at 8 y of age in 198 children from the HOME Study. METHODS:We quantified triclosan in urine samples from mother-child pairs up to nine times between the second trimester of gestation and 8 y of age. The Wechsler Intelligence Scale for Children-IV [i.e., Full-Scale Intelligence Quotient (IQ)] assessment was administered to HOME Study children at 8 y of age. We estimated covariate-adjusted triclosan-IQ associations at each visit. We also tested whether associations between triclosan concentrations and cognitive test scores varied among exposure at different time periods. RESULTS:Full-Scale IQ was not significantly associated with urinary triclosan concentrations during gestation or childhood but was significantly associated with a 10-fold increase in maternal urinary triclosan concentration at delivery [-4.5?points (95% CI: -7.0, -2.0)]. Perceptual Reasoning Index (PRI) scores were significantly decreased in association with urinary triclosan concentrations at delivery and at 2 y of age. Associations between repeated triclosan concentrations and cognitive test scores significantly varied among exposure at different time periods for Full-Scale IQ, PRI, Verbal Comprehension Index, and Working Memory (triclosan-visit interaction p?0.04). CONCLUSION:Urinary triclosan concentrations at delivery, but not during mid to late pregnancy and childhood, were associated with significantly lower children's cognitive test scores at 8 y of age in this cohort of U.S. children. https://doi.org/10.1289/EHP2777.
| S-EPMC6072011 | biostudies-literature
Project description:The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin-proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal function via inhibiting both the 19S proteasome-associated deubiquitinases (USP14 and UCHL5) and the chymotrypsin-like (CT-like) peptidase activity of 20S proteasomes, thereby contributing to bilirubin neurotoxicity. This is supported by multiple lines of evidence. First, sera from patients with hyperbilirubinemia were able to inhibit the peptidase activity of purified 20S proteasome in vitro in a bilirubin concentration-dependent manner; meanwhile, the blood cells of these patients showed significantly increased levels of ubiquitinated proteins (Ub-prs), consistent with proteasome inhibition. Second, intracerebroventricular injection to adult rats or intraperitoneal injections to neonatal rats of bilirubin-induced neural accumulation of Ub-prs, concurrent with other neural pathology; and brain malfunction and pathology induced by neonatal exposure to hyperbilirubinemia were detectable in the rats during their adulthood. Third, in primary cultures of hippocampal neurons, bilirubin strikingly induced Ub-pr accumulation before the activation of cell death pathway becomes discernible. Finally, bilirubin in vitro directly inhibited both the deubiquitination activity of proteasome-associated USP14 and UCHL5 and the CT-like peptidase activity of purified 20S proteasomes, in a dose-dependent manner. Hence, this study has discovered that increased bilirubin at a clinically achievable level can act as a proteasome inhibitor via targeting the 19S proteasome-associated deubiquitinases (DUBs) and, perhaps to a less extent, the 20S proteasome, identifying a novel mechanism for bilirubin neurotoxicity.
| S-EPMC5520929 | biostudies-literature
Project description:Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.
| S-EPMC7772425 | biostudies-literature