Risk Of Neurotoxicity Research Articles

Contrast-Induced Encephalopathy in Patients with Chronic Kidney Disease and End-Stage Kidney Disease: A Systematic Review and Meta-Analysis.

Background: Contrast-induced encephalopathy (CIE) is an infrequent but serious neurological condition that occurs shortly after the administration of contrast during endovascular and angiography procedures. Patients suffering from chronic kidney disease (CKD) or end-stage kidney disease (ESKD) are considered to be at a higher risk of contrast medium neurotoxicity, due to the delayed elimination of the contrast medium. However, the occurrence and characteristics of CIE in CKD/ESKD patients have not been extensively investigated. Methods: We conducted a comprehensive literature search, utilizing databases such as MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, up to September 2022. The purpose was to identify documented cases of CIE among patients with CKD or ESKD. Employing a random-effects model, we calculated the pooled incidence and odds ratio (OR) of CIE in CKD/ESKD patients. Results: Our search yielded a total of eleven articles, comprising nine case reports and two observational studies. Among these studies, 2 CKD patients and 12 ESKD patients with CIE were identified. The majority of the CKD/ESKD patients with CIE (93%) had undergone intra-arterial contrast media and/or endovascular procedures to diagnose acute cerebrovascular disease, coronary artery disease, and peripheral artery disease. The male-to-female ratio was 64%, and the median age was 63 years (with an interquartile range of 55 to 68 years). In the two observational studies, the incidence of CIE was found to be 6.8% in CKD patients and 37.5% in ESKD patients, resulting in a pooled incidence of 16.4% (95% CI, 2.4%-60.7%) among the CKD/ESKD patients. Notably, CKD and ESKD were significantly associated with an increased risk of CIE, with ORs of 5.77 (95% CI, 1.37-24.3) and 223.5 (95% CI, 30.44-1641.01), respectively. The overall pooled OR for CIE in CKD/ESKD patients was 32.9 (95% CI, 0.89-1226.44). Although dialysis prior to contrast exposure did not prevent CIE, approximately 92% of CIE cases experienced recovery after undergoing dialysis following contrast exposure. However, the effectiveness of dialysis on CIE recovery remained uncertain, as there was no control group for comparison. Conclusions: In summary, our study indicates an association between CIE and CKD/ESKD. While patients with CIE showed signs of recovery after dialysis, further investigations are necessary, especially considering the lack of a control group, which made the effects of dialysis on CIE recovery uncertain.

The use of transcutaneous bilirubin nomograms for the prevention of bilirubin neurotoxicity in the neonates.

Although neonatal jaundice is a ubiquitous and predominantly benign phenomenon, the risk of neurotoxicity exists in a number of infants with unconjugated hyperbilirubinemia. Plotting bilirubin values on nomograms enables clinicians to employ an anticipatory and individualized approach with the goal of avoiding excessive hyperbilirubinemia and preventing acute bilirubin encephalopathy and its progression to kernicterus. We aimed to construct nomograms for White term infants based on transcutaneous bilirubin (TcB) measurements using a JM-105 device. TcB measurements were taken in infants at ages ranging from 0 to 96 postnatal hours. We then constructed hour-specific TcB nomograms from forehead and sternum measurements in infants who did not require subsequent phototherapy. We included 2,981 TcB measurements taken on the forehead and 2,977 measurements taken on the sternum in 301 White term newborn infants. We assessed the predictive abilities of the nomograms at six postnatal time intervals using receiver operating characteristic curves. The areas under the curves indicated reasonable prediction of hyperbilirubinemia requiring phototherapy, except for the forehead measurement taken within the first 12 h of life. Sensitivity tended to rise as postnatal age increased. The nomograms illustrate dermal bilirubin dynamics in White term neonates during the first 4 days of life. They may be useful tools to predict individualized risk of hyperbilirubinemia requiring treatment, and to plan optimal follow-up of infants at risk of bilirubin neurotoxicity.

First line treatments in primary central nervous system lymphomas in young patients.

The aim of this review is to provide an update on current first-line treatments as well as on-going studies in immunocompetent patients with primary central nervous system lymphomas. High-dose methotrexate (HD-MTX)-based polychemotherapy is widely used in induction treatment (IT). Among HD-MTX-based regimens, the best association is not yet defined. IT should be followed by a consolidation or a maintenance according to patient's age and performance status. Thiotepa-based intensive chemotherapy (IC) followed by autologous stem cell transplantation (ASCT) has improved survival in eligible patients compared to a nonmyeloablative consolidation. Because of the high risk of neurotoxicity, conventional whole brain radiotherapy (WBRT; 36-40 Gy) has been abandoned. Reduced-WBRT (23.4 Gy) is an alternative option in patients under 60 years-old in complete response after IT. Its safety remains to be demonstrated in elderly patients. The benefit of maintenance strategies to reduce the risk of relapse is being assessed in several studies in patients beyond 70 years-old. HD-MTX-based polychemotherapy remains the corner stone of the IT, but the best regimen is not yet defined. Clinical trials assessing new IT regimens are ongoing. Intensive consolidation with IC + ASCT benefits patients up to 70 years-old. Predictive factors are under investigation to better define therapeutic response and guide treatment adjustment.

Cefepime Population Pharmacokinetics, Antibacterial Target Attainment, and Estimated Probability of Neurotoxicity in Critically Ill Patients.

Cefepime has been reported to cause concentration-related neurotoxicity, especially in critically ill patients with renal failure. This evaluation aimed to identify a dosing regimen providing a sufficient probability of target attainment (PTA) and the lowest justifiable risk of neurotoxicity in critically ill patients. A population pharmacokinetic model was developed based on plasma concentrations over four consecutive days obtained from 14 intensive care unit (ICU) patients. The patients received a median dose of 2,000 mg cefepime by 30-min intravenous infusions with dosing intervals of every 8 h (q8h) to q24h. A time that the free drug concentration exceeds the MIC over the dosing interval (fT>MIC) of 65% and an fT>2×MIC of 100% were defined as treatment targets. Monte Carlo simulations were carried out to identify a dosing regimen for a PTA of 90% and a probability of neurotoxicity not exceeding 20%. A two-compartment model with linear elimination best described the data. Estimated creatinine clearance was significantly related to the clearance of cefepime in nondialysis patients. Interoccasion variability on clearance improved the model, reflecting dynamic clearance changes. The evaluations suggested combining thrice-daily administration as an appropriate choice. In patients with normal renal function (creatinine clearance, 120 mL/min), for the pharmacodynamics target of 100% fT>2×MIC and a PTA of 90%, a dose of 1,333 mg q8h was found to be related to a probability of neurotoxicity of ≤20% and to cover MICs up to 2 mg/L. Continuous infusion appears to be superior to other dosing regimens by providing higher efficacy and a low risk of neurotoxicity. The model makes it possible to improve the predicted balance between cefepime efficacy and neurotoxicity in critically ill patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01793012).

Development of a rat physiologically based kinetic model (PBK) for three organophosphate flame retardants (TDCIPP, TCIPP, TCEP)

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), Tris (1-chloro-2-propyl) phosphate (TCIPP) and tris (2-chloroethyl) phosphate (TCEP) are three widely used organophosphate flame retardants (OPFRs) being frequently detected in human body fluids. Although OPFRs are being detected in human beings, the toxicological effects of their exposure are not clearly understood due to limited data. For this, a physiologically based kinetic model (PBK) was developed in MCSIM integrated with R studio and validated in rats to understand the toxicokinetics of OPFRs for the first time. The model required the enterohepatic recirculation (EHR) mechanism which was included to explain the non-linear data. Model parameters were optimized using the Bayesian framework (Markov Chain Monte Carlo) along with a visual fitting to explain toxicokinetic data. Goodness-of-fit was calculated to evaluate model predictability power in Rstudio. The model can appropriately predict the concentration of OPFRs in several organs like plasma, urine, kidney, etc. within 1–2-fold of experimental data. Slow elimination of OPFRs was observed from adipose tissue and brain at late time points, showing their potential to accumulate upon daily exposure. The use of PBK was demonstrated by reconstructing the oral exposure equivalent to the in-vitro toxic dose to support neurotoxic risk assessment. This version of PBK can be extrapolated to human for toxicological risk assessment. Nonetheless, further investigation is required to understand whether these chemicals follow similar kinetics in humans, which could lead to a greater risk to human health. Code availabilityThe model will be available to access through Rshiny using GIThub soon, InSilicoVida/Flame-Retardant-PBPK-Model: It contains organophosphate flame retardant (OPFRs) PBK for TDCIPP, TCIPP and TCEP (github.com).

Benzene health risk assessment for neurological disorders of gas station employees in Rayong Province, Thailand.

The main job of employees working in the area of fuel service stations is to provide refueling services to customers. Therefore, operators at petrol stations may be exposed to chemicals for long periods, potentially affecting their health in nervous system. This study aims to assess the risk of benzene exposure to the nervous system in gas station operators. Data were collected from 100 fuel service personnel working at fuel dispensers and 100 employees working outside fuel dispensers, accounting to 200 cases. Data were collected using interview questionnaires. Urine samples were used for the analysis of t,t-muconic acid. The results showed that t,t-muconic acid concentration is 431.23 ± 233.69 μg/g.cr (449.28 ± 213.32 μg/g.cr at fuel dispensers vs 413.18 ± 252.20 μg/g.cr outside fuel dispensers). The risk characterization results showed that most of the risks were at level 1 (low risk), as observed in 108 people (54.0%). The results of the analysis of the relationship between t,t-muconic acid concentrations classified by 3 levels of percentile and neurological disorders of the study group, the results showed that there was a statistically significant relationship (p-value <0.05). Therefore, the benzene neurotoxic risk assessment model could be utilized in field practice.

Cadmium, lead, and mercury in two commercial squid species from the north Adriatic Sea (central Mediterranean): contamination levels and health risk assessment

In this study, lead (Pb), cadmium (Cd), and total mercury (Hg) concentrations in European squids (Loligo vulgaris) and flying squids (Todarodes sagittatus) from the northern Adriatic Sea (Italy) were analyzed. The risk of the Italian population being exposed to potentially hazardous metal concentrations through the consumption of these products was also assessed. Compared to European squids, flying squids showed three times higher total Hg concentrations and one hundred times higher Cd concentrations to the point that more than 6 and 25% of the samples exceeded the maximum Hg and Cd limits established by the current legislation. From the evaluation of dietary exposure levels, it emerged that the consumption of flying squids was associated with the highest Pb intake by children and, consequently, with the lower margin of exposure values in relation to the risk of neurotoxicity (margin of exposure=33). Consumption of flying squids, especially by children, was also associated with higher intakes of Cd, inorganic, and methyl-Hg, which, respectively, accounted for 156, 113, and 23% of the tolerable weekly intakes established for these contaminants at European level. The obtained results raise concern and it may be necessary to provide specific dietary advice on the moderate dietary consumption of some cephalopod species, especially to the youngest and most vulnerable segment of the population. However, besides the highly conservative deterministic method adopted in this study, a refined consumer exposure assessment should be performed through the probabilistic methodology, which is more suitable to represent the real exposure scenario.

Neurotoxicity in patients with CNS lymphomas treated with CAR‐T cell therapy. A LOC network study

Introduction: CAR-T cell therapy represents one of the major progress of the last years in aggressive B-cell lymphomas. Its use in central nervous system (CNS) lymphomas has been limited due to the fear of neurotoxicity but several recent studies have showed promising efficacy in this setting. The aim of this study was to focus on neurotoxicity in CNS lymphoma patients treated with CAR-T cells. Methods: Patients with isolated CNS relapse of DLBCL treated with commercial CAR-T cells at Pitié-Salpêtrière hospital were retrospectively selected. We considered only neurological deterioration for which other causes than CAR-T cell toxicity had been reasonably ruled out. Results: Thirty patients (median age: 65, 17 women, 19 primary, 11 secondary CNS lymphomas, median of 3 previous lines) received CAR-T cells (Tisa-cel: N = 23, axi-cel, N = 7) between May 2020 and December 2022. At the time of CAR-T, 15 (50%) had stable or progressive disease, median Karnofsky Performance Status (KPS) was 70, median Montreal Cognitive Assessment (MoCA) score was 22 and median immune effector cell-associated encephalopathy (ICE) score was 10. Twelve (40%) patients didn’t experience any neurotoxicity after CAR-T, whereas 9 (30%), 3 (10%), 2 (7%), 4 (13%) patients experienced grade 1, 2, 3 or 4 toxicity according to ASTCT classification. The signs of neurotoxicity began at a median of 5 days after CAR-T. The most common symptoms were cognitive disorders (N = 18), motor deficit (N = 4), balance disorders (N = 8), consciousness disorders (N = 5), seizures (N = 3) and movement disorders (N = 3). Among cognitive symptoms, there was predominantly a worsening of pre-existing symptoms regarding memory impairment (12/15 patients) or dysexecutive syndrome (11/13), while dysgraphia or dyscalculia were most frequently new symptoms (in 14/15 and 7/11 patients). Brain MRI showed pseudo-progression in 4 cases. On lumbar puncture, median IL-6 level and median cellularity were higher in patients with grade 2 to 4 neurotoxicity compared to other patients (243 vs. 41 pg/ml, 15 vs. 3 cells/mm3). We found no association between risk of neurotoxicity and age, gender, pre-CART KPS, MoCA or ICE score, primary vs. secondary CNS lymphoma or type of CAR-T. Twelve patients (40%) received steroids, for a median of 10 days, leading to an improvement in a median of 5 days; one received anakinra. Median duration with neurological impairment was 13 days, but was >3 months in 3 patients, including one who finally died from neurotoxicity. Conclusions: The majority of CNS lymphoma patients didn’t experience severe neurotoxicity following CAR-T cells, so that this treatment shouldn’t be contraindicated in this population. However, the percentage of severe and prolonged neurotoxicity is probably higher than in systemic lymphomas and a close neurological follow-up is warranted in these complex situations. Further studies are needed to better predict severe neurotoxicity. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. S. Choquet Consultant or advisory role: Kite-Gilead, Novartis

Ertapenem blood concentration: a retrospective cohort study to analyze risk of neurotoxicity.

Several cases of ertapenem-related neurotoxicity have been published in the current literature. However, studies evaluating the ertapenem blood concentration (EBC) as a risk of these adverse events are scarce. We aimed to evaluate the relationship between the trough EBC and the risk of neurological toxicity. Retrospective study, including patients who underwent ertapenem treatment between october 2019 and february 2021. We excluded patients in the critical care unit and those whose blood sample were not properly taken in order to analyze ertapenem trough concentration. We also excluded patients whose clinical follow-up was not properly realized for the entire period of ertapenem treatment. The main outcome was the presence of any suspicious neurological side effect owing to ertapenem administration and its relationship with the plasma concentration. Secondary outcomes were to identify clinical and analytical data contributing to a higher risk of neurotoxicity. The initial cohort was composed by 158 individuals. For the final analysis we evaluated 102 patients, reporting a neurological alteration in 13/102 (12.7%). Mean trough EBC was significantly higher in patients showing neurotoxicity in comparison with those who did not (37.8 mcg ml-1 SD±35.7 vs 14.6 mcg ml-1 SD±15.2; p=0.002). In multivariable logistic regression analysis, EBC (OR= 1.07; p=0.006), a moderate renal insuficiency (OR= 9.2; p=0.02) and a history of previous neurologic disease (OR=9.9;p=0.02) were identified as risk factors of neurological alteration during ertapenem treatment. In patients at risk, determining the ertapenem plasma concentration may help to minimize the risk of neurotoxicity.

Impact of Protein Binding Capacity and Daily Dosage of a Drug on Total Serum Bilirubin Levels in Susceptible Infants.

Hyperbilirubinemia is a common pathological condition in neonates. Free bilirubin can penetrate the blood-brain barrier (BBB), which can lead to bilirubin neurotoxicity. In the context of predicting the risk of bilirubin neurotoxicity, although the specificity and sensitivity of free bilirubin levels are higher than those of total serum bilirubin (TSB), free bilirubin is not widely monitored in clinical practice. The threshold TSB levels at which phototherapy must be administered have been established previously. However, TSB levels are not well correlated with neurodevelopmental outcomes. Currently, TSB levels are commonly used to guide phototherapy for neonatal hyperbilirubinemia. Some clinical drugs can displace bilirubin from its albumin-binding sites, and consequently upregulate plasma bilirubin. Daily dosages play a vital role in regulating bilirubin levels. A drug with both a high protein binding capacity and high daily dosage significantly increases bilirubin levels in infants. Premature or very low birth weight (VLBW) infants are vulnerable to the upregulation of bilirubin levels as they exhibit the lowest reserve albumin levels and consequently the highest bilirubin toxicity index. Because bilirubin is involved in maintaining the balance between pro-oxidant and antioxidant agents, the downregulation of bilirubin levels is not always desirable. This review provides insights into the impact of protein binding capacity and daily dosage of drugs on the bilirubin levels in susceptible infants.

Single fraction stereotactic radiosurgery and fractionated stereotactic radiotherapy provide equal prognosis with overall survival in patients with brain metastases at diagnosis without surgery at primary site.

Stereotactic radiosurgery (SRS) and fractionated stereotactic radiation therapy (SRT) are both treatments shown to be effective in treating brain metastases (BMs). However, it is unknown how these treatments compare in effectiveness and safety in cancer patients with BMs regardless of the primary cancer. The main objective of this study is to investigate the SRS and SRT treatments' associations with the overall survival (OS) of patients diagnosed with BMs using the National Cancer Database (NCDB). Patients in the NCDB with breast cancer, non-small cell lung cancer, small cell lung cancer, other lung cancers, melanoma, colorectal cancer, or kidney cancer who had BMs at the time of their primary cancer diagnosis and received either SRS or SRT as treatment for their BMs were included in the study. We analyzed OS with a Cox proportional hazard analysis that adjusted variables associated with improved OS during univariable analysis. Of the total 6,961 patients that fit the criteria for the study, 5,423 (77.9%) received SRS and 1,538 (22.1%) received SRT. Patients who received SRS treatment had a median survival time of 10.9 (95% CI [10.5-11.3]), and those who received SRT treatment had a median survival time of 11.3 (95% CI [10.4-12.3]) months. This difference was not found to be significant (Log-rank P=0.31). Multivariable Cox proportional hazard analysis did not yield a significant difference between the treatments' associations with OS (Hazard Ratio: 0.942, CI 95% [0.882-1.006]; P=.08) or SRS vs. SRT. In this analysis, SRS and SRT did not show a significant difference in their associations with OS. Future studies investigating the neurotoxicity risks of SRS as compared to SRT are warranted.

Neurocytotoxicity of imidacloprid- and acetamiprid-based comercial insecticides over the differentiation of SH-SY5Y neuroblastoma cells

Neonicotinoids are effective insecticides with specificity for invertebrate nicotinic acetylcholine receptors. Neonicotinoids are chemically stable and tend to remain in the environment for long so concerns about their neurotoxicity in humans do nothing but increase. Herein, we evaluated the chronic toxic effects of acetamiprid- and imidacloprid-based insecticides over the differentiation of human neuroblastoma SH-SY5Y cells, which were exposed to these insecticides at a concentration range similar to that applied to crop fields (0.01–0.5 mM). Both insecticides did not have acute cytotoxic effects in both non-differentiated and in staurosporine-differentiated SH-SY5Y cells cytotoxicity as measured by the MTT and vital-dye exclusion tests. However, after a chronic (7-day) treatment, only imidacloprid dose-dependently decreased the viability of SH-SY5Y cells (F(4,39) = 43.05, P < 0.001), largely when administered-during cell differentiation (F(4,39) = 51.86, P < 0.001). A well-defined dose-response curve was constructed for imidacloprid on day 4 (R2 = 0.945, EC50 = 0.14 mM). During differentiation, either imidacloprid or acetamiprid dose-dependently caused neurite branch retraction on day 3, likely because of oxidative stress, to the extent that cells turned into spheres without neurites after 7-day treatment. Despite their apparent safety, the neurodevelopmental vulnerability of SH-SY5Y neurons to the chronic exposure to imidacloprid and to a lesser extent to acetamiprid points to a neurotoxic risk for humans.

Little known and less understood: the benefits of a lower hematocrit (~40%) in reconstituted blood for double volume exchange transfusion.

A double volume exchange transfusion (DVET) is an important, if infrequently performed, intervention to acutely lessen the total serum bilirubin (TSB) and reduce the extravascular CNS bilirubin exposure when neonatal hyperbilirubinemia poses a neurotoxicity risk. The current analysis based on the seminal works of Valaes, and Sproul and Smith, predicts that a DVET blood product of lower hematocrit (~40%) via its greater plasma volume and corresponding higher albumin content optimizes the benefits of an DVET in several ways. First, by augmenting bilirubin clearance from the extravascular space and thereby further reducing the CNS bilirubin exposure, second, by favorably positioning the intravascular albumin-bilirubin binding capacity at DVET completion to accommodate additional bilirubin equilibration and rebound hyperbilirubinemia post-exchange, and third by correcting anemia if present.

Single-Session Gamma Knife Radiosurgery for Patients With 20 or More Brain Metastases.

Stereotactic radiosurgery (SRS) is a widely accepted treatment modality for brain metastases. The role of SRS in patients with higher numbers of metastases remains controversial. To define outcomes in patients with ≥20 brain metastases managed using single-session SRS. This single-institution retrospective cohort study studied 75 patients (26 non-small-cell lung cancer, 21 small-cell lung cancer, 14 breast cancer, and 14 melanoma) undergoing single-session SRS. The median number of tumors per patient was 24, and the median cumulative tumor volume was 3.70 cc. The median margin dose prescribed to each individual tumor was 16 Gy. The median integral cranial dose was 5492 mJ. The median beam on time was 160 minutes. Univariate and multivariate analyses were performed with significance set at P < .05. The median overall survival after SRS was 8.8 months (patients with non-small-cell lung cancer), 4.6 months (patients with small-cell lung cancer), 11.3 months (patients with breast cancer), and 4.1 months (patients with melanoma). Primary cancer type, number of brain metastases, and concurrent immunotherapy were significant factors in predicting survival. Local tumor control rate per patient was 97.3% and 94.6% at 6 and 12 months after SRS, respectively. Thirty-six patients underwent additional SRS for new tumor development with a median time after SRS of 5 months. Three patients experienced adverse radiation events. Single-session SRS is a well-tolerated palliative treatment option even in patients with ≥20 brain metastases, achieving local control rate >90% with low risks of neurotoxicity while continuing concurrent systemic oncological care.

Neurofilament Light Chain: A Translational Safety Biomarker for Drug-Induced Peripheral Neurotoxicity.

Branaplam is a splicing modulator previously under development as a therapeutic agent for Spinal Muscular Atrophy Type 1 and Huntington's disease. Branaplam increased the levels of survival motor neuron protein in preclinical studies and was well tolerated in early clinical studies; however, peripheral neurotoxicity was observed in a preclinical safety study in juvenile dogs. The aim of this study was to determine whether serum neurofilament light chain (NfL) concentrations in dogs could serve as a monitoring biomarker for branaplam-induced peripheral neurotoxicity. A 30-week time-course investigative study in dogs treated with vehicle control (negative control), neurotoxic pyridoxine (positive control), or branaplam was conducted to assess neuropathology, nerve morphometry, electrophysiological measurements, gene expression profiles, and correlation to NfL serum concentrations. In branaplam-treated animals, a mild to moderate nerve fiber degeneration was observed in peripheral nerves correlating with increased serum NfL concentrations, but there were no observed signs or changes in electrophysiological parameters. Dogs with pyridoxine-induced peripheral axonal degeneration displayed clinical signs and electrophysiological changes in addition to elevated serum NfL. This study suggests that NfL may be useful as an exploratory biomarker to assist in detecting and monitoring treatment-related peripheral nerve injury, with or without clinical signs, associated with administration of branaplam and other compounds bearing a neurotoxic risk.

Amoxicillin-Induced Neurotoxicity: Contribution of a Healthcare Data Warehouse to the Determination of a Toxic Concentration Threshold.

Amoxicillin (AMX)-induced neurotoxicity is well described and may be associated with AMX overexposure. No neurotoxic concentration threshold has been determined thus far. A better knowledge of maximum tolerable AMX concentrations is of importance to improve the safety of high doses of AMX. We conducted a retrospective study using the local hospital data warehouse EhOP® to generate a specific query related to AMX neurotoxicity symptomatology. All patient medical reports containing a mention of neurotoxicity clinical symptoms coupled with AMX plasma concentration measurements were explored. Patients were classified into two groups according to the imputability of AMX in the onset of their neurotoxicity, on the basis of chronological and semiological criteria. A receiver-operating characteristic curve was performed to identify an AMX neurotoxic steady-state concentration (Css) threshold. The query identified 101 patients among 2054 patients benefiting from AMX TDM. Patients received a median daily dose of 9 g AMX, with a median creatinine clearance of 51 mL/min. A total of 17 of the 101 patients exhibited neurotoxicity attributed to AMX. The mean Css was higher for patients with neurotoxicity attributed to AMX (118 ± 62 mg/L) than those without 74 ± 48 mg/L (p = 0.002). A threshold AMX concentration of 109.7 mg/L predicted the occurrence of neurotoxicity. This study identified, for the first time, an AMX Css threshold of 109.7 mg/L associated with an excess risk of neurotoxicity. This approach needs to be confirmed by a prospective study with systematic neurological evaluation and TDM.

The peculiar challenge of bringing CAR-T cells into the brain: Perspectives in the clinical application to the treatment of pediatric central nervous system tumors.

Childhood malignant brain tumors remain a significant cause of death in the pediatric population, despite the use of aggressive multimodal treatments. New therapeutic approaches are urgently needed for these patients in order to improve prognosis, while reducing side effects and long-term sequelae of the treatment. Immunotherapy is an attractive option and, in particular, the use of gene-modified T cells expressing a chimeric antigen receptor (CAR-T cells) represents a promising approach. Major hurdles in the clinical application of this approach in neuro-oncology, however, exist. The peculiar location of brain tumors leads to both a difficulty of access to the tumor mass, shielded by the blood-brain barrier (BBB), and to an increased risk of potentially life-threatening neurotoxicity, due to the primary location of the disease in the CNS and the low intracranial volume reserve. There are no unequivocal data on the best way of CAR-T cell administration. Multiple trials exploring the use of CD19 CAR-T cells for hematologic malignancies proved that genetically engineered T cells can cross the BBB, suggesting that systemically administered CAR-T cell can be used in the neuro-oncology setting. Intrathecal and intra-tumoral delivery can be easily managed with local implantable devices, suitable also for a more precise neuro-monitoring. The identification of specific approaches of neuro-monitoring is of utmost importance in these patients. In the present review, we highlight the most relevant potential challenges associated with the application of CAR-T cell therapy in pediatric brain cancers, focusing on the evaluation of the best route of delivery, the peculiar risk of neurotoxicity and the related neuro-monitoring.

Gamma Knife radiosurgery for gynecologic metastases to the brain: Analysis of pathology, survival, and tumor control

ObjectiveThis study aims to evaluate the efficacy of stereotactic radiosurgery (SRS) in improving health outcomes of patients with gynecologic brain metastases. MethodsPatients with gynecologic metastases treated with SRS from 2008 to 2020 were retrospectively reviewed. The median age at SRS was 63 years old (cervical 45.5, endometrial 65.5, ovarian 61). The median number of tumors was 3 (range 1–27), and cumulative tumor volume was 2.33 cc (range 0.03–45.63). Median margin dose prescribed was 16 Gy (range 14 Gy – 20 Gy). The median 12 Gy volume was 7.30 cc (range 0.21–74.14 cc). Outcome variables included overall survival (OS) after SRS, local tumor control (LTC), distant tumor control, and adverse radiation effect (ARE). ResultsFifty patients (4 cervical, 25 endometrial, and 21 ovarian cancer) were identified. The OS at 6 and 12 months after SRS was 48%, and 44%, respectively. Eight patients (16%) died from CNS disease progression. The number of brain metastases (p = 0.011) and the Karnofsky Performance Scale (KPS) ≥ 70 (p = 0.020) were significant predictors of OS. LTC rate at 6 and 12 months were 92%, and 87%, respectively. Margin dose ≥16Gy correlated with significantly better local tumor control (p = 0.0001) without increased risk of ARE (p = 0.055). The risk of developing new metastases at 6 and 12 months were 12% and 24% respectively. SRS-induced ARE events occurred in 7 patients. ConclusionIntracranial metastases from gynecologic malignancy can be effectively treated using SRS with low risk of neurotoxicity. Margin dose ≥16Gy can provide significantly better tumor control. Repeat SRS can be utilized to treat new metastases while avoiding the potential cognitive symptoms associated with WBRT.

Dithianon exposure induces dopaminergic neurotoxicity in Caenorhabditis elegans

Dithianon is a conventional broad-spectrum protectant fungicide widely used in agriculture, but its potential neurotoxic risk to animals remains largely unknown. In this study, neurotoxic effects of Dithianon and its underlying cellular and molecular mechanisms were investigated using the nematode, Caenorhabditis elegans, as a model system. Upon chronic exposure of C. elegans to Dithianon, dopaminergic neurons were found to be vulnerable, with significant degeneration in terms of structure and function in a concentration-dependent manner. In examining toxicity mechanisms, we observed significant Dithianon-induced increases in oxidative stress and mitochondrial fragmentation, both of which are often associated with cellular stress. The present study suggests that Dithianon exposure causes dopaminergic neurotoxicity in C. elegans, by inducing oxidative stress and mitochondrial dysfunction. These findings contribute to a better understanding of Dithianon's neurotoxic potential.

Dissecting the Enantioselective Neurotoxicity of Isocarbophos: Chiral Insight from Cellular, Molecular, and Computational Investigations.

Chiral organophosphorus pollutants are found abundantly in the environment, but the neurotoxicity risks of these asymmetric chemicals to human health have not been fully assessed. Using cellular, molecular, and computational toxicology methods, this story is to explore the static and dynamic toxic actions and its stereoselective differences of chiral isocarbophos toward SH-SY5Y nerve cells mediated by acetylcholinesterase (AChE) and further dissect the microscopic basis of enantioselective neurotoxicity. Cell-based assays indicate that chiral isocarbophos exhibits strong enantioselectivity in the inhibition of the survival rates of SH-SY5Y cells and the intracellular AChE activity, and the cytotoxicity of (S)-isocarbophos is significantly greater than that of (R)-isocarbophos. The inhibitory effects of isocarbophos enantiomers on the intracellular AChE activity are dose-dependent, and the half-maximal inhibitory concentrations (IC50) of (R)-/(S)-isocarbophos are 6.179/1.753 μM, respectively. Molecular experiments explain the results of cellular assays, namely, the stereoselective toxic actions of isocarbophos enantiomers on SH-SY5Y cells are stemmed from the differences in bioaffinities between isocarbophos enantiomers and neuronal AChE. In the meantime, the modes of neurotoxic actions display that the key amino acid residues formed strong noncovalent interactions are obviously different, which are related closely to the molecular structural rigidity of chiral isocarbophos and the conformational dynamics and flexibility of the substrate binding domain in neuronal AChE. Still, we observed that the stable "sandwich-type π-π stacking" fashioned between isocarbophos enantiomers and aromatic Trp-86 and Tyr-337 residues is crucial, which notably reduces the van der Waals' contribution (ΔGvdW) in the AChE-(S)-isocarbophos complexes and induces the disparities in free energies during the enantioselective neurotoxic conjugations and thus elucidating that (S)-isocarbophos mediated by synaptic AChE has a strong toxic effect on SH-SY5Y neuronal cells. Clearly, this effort can provide experimental insights for evaluating the neurotoxicity risks of human exposure to chiral organophosphates from macroscopic to microscopic levels.