Risk Of Neurotoxicity Research Articles

Psychoactive Bath Salts and Neurotoxicity Risk.

Synthetic cathinones are new designer drugs that possess hallucinogenic and psychostimulant properties, and are designed to mimic the effects of illegal substances such as cocaine, amphetamines, and 3.4-methylenedioxymethamphetamine (ecstasy) and to produce rewarding effects, circumventing existing laws and penalties. Synthetic cathinones, also referred to as 'bath salts', have become popular particularly among young people since the mid-2000s. Similar to other psychomotor stimulants, synthetic cathinones have the potential to increase monoamine concentration in the synaptic cleft by targeting the plasma membrane transporters of dopamine, norepinephrine, and serotonin. Because of their structural similarities to amphetamines, it has been suggested that synthetic cathinones may have a neurotoxicity profile similar to that of their amphetamine congeners. Therefore, it has been hypothesized that synthetic cathinones may induce neurotoxicity on monoamine nerve endings in the striatum, hippocampus, and cortex. To date, with regard to synthetic cathinone neurotoxicity, parameters such as monoamine depletion, biosynthetic enzyme inhibition, cytotoxicity, generation of reactive oxygen species, pro-oxidation status, and the ability to induce neuroinflammation were investigated in both in vitro and in vivo experimental studies. Compared with amphetamines, synthetic cathinones appear to have more moderate effects than their amphetamine congeners in terms of neurotoxic effects. However, many synthetic cathinone users take these substances simultaneously with other substances such as benzodiazepines, amphetamines, ecstasy, tetrahydrocannabinol, and ethanol and this abuse can modify their neurotoxic effects. Hence, it is important to understand the underlying mechanism of early neurotoxic effects in case of polysubstance use. In this review, we aimed to present up-to-date information on the abuse potential of synthetic cathinones, their legal status, mechanism of action, and particularly their neurotoxic effects.

Brain Organoid‐on‐a‐Chip: Model System for Predicting cART induced Neurotoxicity and Neuropsychiatric Effects

The current combination of antiretroviral therapy (cART) therapy comes with its benefits along with its side effect, e.g. neurotoxicity issues that lead to the progressive loss of neurons in HIV‐infected individuals and leads to neuropsychiatric adverse effects (NP‐AE)(e.g. depression, anxiety, and mood disorders, etc.) on a long‐term basis. Furthermore, due to the limitation of the resemblance of animal models to human biology (due to species differences) and unavailability of the robust humanized HIV‐1 infected mouse model. We have proposed a new strategy to generate human induced pluripotent stem cells (hiPSCs)‐derived brain organoids in a controlled manner by combining stem cell biology with lab‐on‐a‐chip technology, thereby creating a brain‐organoid‐on‐a‐chip system (Shown in Fig. 1). The innovative part of this project is the organoid vascularization by growing them directly on the microfluidic chip in Matrigel under the controlled milieu of growth factors/ nutrient molecules, thus, facilitating the angiogenesis like process. The organoids were generated as per published Lancaster protocol with minor lab modification and characterized for pluripotent markers (NANOG, OCT‐4, SOX2, KLF4, etc.) using RT‐PCR assay and immunofluorescence for the characterization of the key markers of human brain via the expression of neuronal progenitor’s (SOX2), a cortical proliferating neuronal (TUJ1), forebrain (FOXG1) and hippocampus (PROX1) neuronal lineage markers. Using the developed brain organoids, we have determined the effect of combination cART therapy on the increased risk of neurotoxicity using the CSF concentration of marketed cART regimen, i.e. EVF‐13.85 ng/ml, TDF‐5 ng/ml; FTC‐109 ng/ml; DOR‐35.4 ng/ml; 3TC‐46 ng/ml; EVG‐25 ng/ml; TAF‐20 ng/ml) up to day 7. Results showed that organoids treated with single component or cART combination, resulted in significant loss of dendrites, increased beading, shrinkage of neuropil and lower cell viability for day 7 > day 1 in cART treated samples compared to control samples. Similarly, we also have analyzed other marketed cART combination, they also showed loss of MAP‐2 staining (neuron marker for neurogenesis) for day‐7 treated samples. As the literature suggests, Efavirenz (non‐nucleoside reverse transcriptase inhibitors; NNRTIs) and Dolutegravir (Integrase Inhibitors) have shown more neuropsychic adverse effect in HIV patient’s early or later stages of the treatment. We also, checked the effect of EVF toxicity using two different concentration (i.e. 10 ng/ml and 30 ng/ml) dose up to 7 days and measured the cell number and neurite growth as a toxicity parameter. Our results showed that 30 ng/ml treated samples showed loss of neurite length in a very significant manner even on day 3 and continued until day 7. However, for lower concentration (10 ng/ml), day 7 showed significant loss in neurite length compared to day 1. For future studies, we will be studying the long term c ART toxicity and try to establish a correlation of the molecular markers and gene expression profiles (as mentioned in Fig. 2), as an indicator for cART‐associated neuropsychiatric adverse events (NP‐AEs).Support or Funding InformationSOP‐Office of Science Research Award and start‐up funds from SOP, TTUHSC, TX.Schematic diagram of organoid‐on‐a‐chip model to study cART toxicity leading to NP‐AE’sFigure 1Key factors (neurotransmitters or molecular biomarkers) associated with cART toxicity leading to NP‐AE’s to be studied using organoid‐on‐a‐chip modelFigure 2

How Should Trainees' Influences on Postoperative Outcomes Be Disclosed?

Conflict arises when surgeons and anesthesiologists disagree about goals of care in perioperative settings. Collaboration is essential for safe, efficient, and effective care. Drawing on 2 pediatric cases that highlight risks of anesthetic exposure, this article examines the influence of surgical training on outcomes, barriers to collaboration, and anesthesiologists' ethical obligations to educate surgeons and parents about anesthesia-induced neurotoxicity risks. The article also discusses how to align surgical and anesthetic practice during surgeries with prolonged anesthetic use.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) acutely affect human \u03b11\u03b22\u03b32L GABAA receptor and spontaneous neuronal network function in vitro

Concerns about the neurotoxic potential of polyfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) increase, although their neurotoxic mechanisms of action remain debated. Considering the importance of the GABAA receptor in neuronal function, we investigated acute effects of PFAS on this receptor and on spontaneous neuronal network activity. PFOS (Lowest Observed Effect Concentration (LOEC) 0.1 µM) and PFOA (LOEC 1 µM) inhibited the GABA-evoked current and acted as non-competitive human GABAA receptor antagonists. Network activity of rat primary cortical cultures increased following exposure to PFOS (LOEC 100 µM). However, exposure of networks of human induced pluripotent stem cell (hiPSC)-derived neurons decreased neuronal activity. The higher sensitivity of the α1β2γ2L GABAA receptor for PFAS as compared to neuronal networks suggests that PFAS have additional mechanisms of action, or that compensatory mechanisms are at play. Differences between rodent and hiPSC-derived neuronal networks highlight the importance of proper model composition. LOECs for PFAS on GABAA receptor and neuronal activity reported here are within or below the range found in blood levels of occupationally exposed humans. For PFOS, LOECs are even within the range found in human serum and plasma of the general population, suggesting a clear neurotoxic risk.

Effect of Cefepime on Neurotoxicity Development in Critically Ill Adults With Renal Dysfunction

Pharmacodynamic and pathophysiologic changes in critically ill adults receiving cefepime may increase the risk of adverse events. What is the impact of cefepime exposure on neurotoxicity development in critically ill adults with renal dysfunction? Critically ill adults with creatinine clearance< 60mL/min who received cefepime for≥ 48 hours between January 1, 2014 and July 31, 2018 were evaluated for cefepime-associated neurotoxicity (CAN) development. Higher- and lower-dose cefepime exposure groups stratified by moderate (≥ 8g vs< 8g in first 48 hours) or severe (≥ 4g vs< 4g in first 48 hours) renal dysfunction were compared. Between-group comparisons were performed using Fisher exact tests. CAN-free survival was evaluated using Kaplan-Meier curves and log-rank tests. Cefepime total dose in the first 48 hours was greater in the higher-dose cefepime group (3.7 ± 1.6g vs7.7 ± 2.2 g; P< .001). Cefepime-associated neurotoxicity occurred infrequently in both lower- (n= 108) and higher-dose (n= 92) cefepime groups (4%vs10%, OR 2.82, 95%CI, 0.84-9.48, P= .093). The frequencies of cefepime-associated neurotoxicity were similar between lower- and higher-dose cefepime groups when moderate renal dysfunction subgroups were compared (5%vs7%, OR 1.42, 95%CI, 0.34-5.92, P= .72) and numerically greater in the higher-dose cefepime group in the severe renal dysfunction subgroup (0 vs16%, P= .064). Times to cefepime-associated neurotoxicity development and resolution were similar between lower- and higher-dose groups. Durations of CAN-free survival were similar between lower- and higher-dose groups. Most patients who developed cefepime-associated neurotoxicity displayed altered mental status (n= 12, 92%). Cefepime-associated neurotoxicity is an uncommon occurrence in critically ill adults. Patients with severe renal dysfunction receiving higher-dose cefepime may be at greater risk of cefepime-associated neurotoxicity, although this requires additional investigation.

Beyond CAR T-Cell Therapy: Continued Monitoring and Management of Complications.

Chimeric antigen receptor (CAR) T-cell therapy has recently emerged as a groundbreaking treatment for CD19-expressing hematologic malignancies and received rapid approval by the U.S. Food & Drug Administration. Tisagenlecleucel and axicabtagene ciloleucel are now widely available at CAR T-cell therapy centers around the United States. Many patients have achieved complete response or remission despite failing multiple previous lines of therapy, but some patients endure the severe risks of cytokine release syndrome, neurotoxicity, and other immunologic effects. As more patients receive this therapy, they will present to their primary oncologists in the community setting for continued follow-up. Oncology-trained advanced practitioners must then have a working knowledge of CAR T-cell therapy, its toxicities, and follow-up care. This review presents the CAR T-cell therapy development and infusion process with associated immediate management. In addition, patient assessment and disease monitoring, relevant diagnostics, unique grading systems to CAR T-cell therapy toxicities, indications for hospitalization, infection prophylaxis, and management of nonneutropenic and neutropenic fever are presented.

A prospective study on treatment of recurrent epithelial ovarian cancer with gemcitabine and pegylated liposomal doxorubicin

Background: Rechallenge of a platinum-based chemotherapy is the most common approach for a recurrent platinumsensitive epithelial carcinoma ovary. However, this carries a substantial risk of cumulative neurotoxicity. Objectives: In the present study, we tried to compare the efficacy and toxicities of gemcitabine pegylated liposomal doxorubicin combination regimen to rechallenge of paclitaxel-carboplatin in this setting. Materials and Methods: A total of 30 patients were included in the study. The patients were randomized into two groups each containing 15 patients. The study group received injection gemcitabine at the dose of 1 g/m2 injection intravenously on day 1 and day 8 and liposomal doxorubicin 30 mg/m2 on day 1 in a 3 weekly cycle up to a total of six cycles in absence of disease progression or unacceptable toxicities. The control group patients were treated with injection paclitaxel at a dose of 175 mg/m2 I/V infusion and injection carboplatin at a dose considering area under the curve 6 in a 3 weekly for six cycles. Results: In the study arm, out of 14 patients, 4 (28.57%) patients had complete response, 6 (42.85%) had partial response, 3 (21.42%) had stable disease, and 1 (7.14%) showed disease progression. In the control arm, 6 (40%) patients out of 15 showed complete response, and 4 (26.66%) partial response. Disease progression was noted in 1 (6.66%) patient. There was less incidence of neurotoxicity compared to the control arm. Conclusion: Chemotherapy with a combination of gemcitabine and pegylated liposomal doxorubicin shows equivalent efficacy in platinum-sensitive recurrent ovarian cancer when compared to rechallenge of platinum-based chemotherapy. The regimen has an acceptable toxicity profile with lesser incidence of neuropathy than rechallenge of paclitaxel-carboplatin combination.

Neurotoxicity of Drugs in Children During Antenatal and Postnatal Development Periods

Neurotoxicity is not rare and periodically severe and even life-threatening adverse effect (AE) of drugs belonging to many therapeutic groups. Manifestations of neurotoxicity are variable: disturbances of peripheral nervous system (ototoxicity and ophtalmotoxicity, visceral neuropathy, neuromuscular blockade), involving of central nervous system (CNS) (developmental brain malformations, seizures, impairment of consciousness, nonspecific encephalopathy). In the way of its consequences central nervous system damage is the most severe manifestation of drug neurotoxicity but the main predisposing factor is related to immature but growing intensively child brain of first years of life; the primary factor for neurotoxic effect is the capacity of drugs to transfer through brain-blood barrier and cumulate into CNS. The principal mechanism of neurotoxicity is dysfunction/apoptosis of nervous cells. Aim of this survey is to provide data and attract once again the professionals attention to the neurological complications of those drugs in the first place that are mainly targeted to the CNS effects (anticonvulsants, antidepressants, antipsychotic drugs, anesthetics) among the mostly sensitive groups – pregnant women, newborns, infants. Results. Based on analyzed data it was revealed high incidence of CNS complications both transient (seizures, temporarily impairment of consciousness) and persistent (developmental brain malformations, decrease of cognitive functions) in case of use of the drugs of current interest (anticonvulsants, antidepressants, antipsychotics, anesthetics (general and local), antibiotics) in risk groups – fetus, newborns, infants. Population risk of neurotoxicity includes also ethnic and genetic special features, renal and hepatic failure, background neuropsychic diseases except determined age groups. Conclusion. Neurotoxicity is one of the most severe manifestations of drug intolerance that depends on different aspects. The youngest targeted group is children of 0 – 3 years old due to their developmental immature brain and age-dependent specific characteristics of pharmacodynamics and pharmacokinetics that could result in drug overdose as a particular case of neurotoxicity due underestimation of the mentioned above factors.

ML-08 THE ROLE OF MAINTENANCE HIGH-DOSE METHOTREXATE CHEMOTHERAPY IN ELDERLY PRIMARY CNS LYMPHOMA PATIENTS

BACKGROUNDThe addition of high-dose methotrexate (HD-MTX)-based chemotherapy to whole brain irradiation (WBRT) has improved the prognosis of primary central nervous system lymphoma (PCNSL). However, the high neurotoxicity rates observed, especially in the elderly, raised interest in chemotherapy-only treatments. Withholding radiotherapy substantially decreases the risk of neurotoxicity, however, disease control may be compromised. In the elderly who cannot tolerate WBRT as a consolidation, maintenance treatment may serve as a feasible approach after an initial response. We treated ePCNSL with induction immunochemotherapy, maintenance chemotherapy with HD-MTX and deferred WBRT. Here, we retrospectively investigated the prognosis for ePCNSL that became CR after the induction chemotherapy.MATERIAL AND METHODSNewly diagnosed ePCNSL (median age: 74 years) received biweekly rituximab/HD-MTX for 6 cycles (induction) followed by monthly rituximab/HD-MTX for 2 cycles (consolidation) and then were treated differently according to the radiological response. With CR patients, HD-MTX was continued with every 3 months (maintenance) for 2 years. Patients who did not obtain consent for maintenance therapy were followed up. For PD patients, immunochemotherapy was interrupted and WBRT initiated immediately. Patients with PR and SD were treated with alternative chemotherapy with temozolomide and/or stereotactic radiotherapy or WBRT.RESULTSThe median PFS was 24.6 months and median OS was 27 months for the entire cohort. Of the 42 ePCNSL, 26 had CR after induction and consolidation, of which 18 cases were carried out maintenance (M+) and 8 cases were followed up (M-). Median PFS was 73 months in the M+ group and 24.5 months in the M- group. Median OS is 102.2months versus 27.6 months, respectively. Both mPFS (P= 0.0125) and mOS (P =0.0015) were significantly prolonged by maintenance therapy.CONCLUSIONIt was suggested that maintenance treatment with HD-MTX may improve the prognosis for ePCNSL that reached complete response after induction therapy.

Traceability of the output concentration of mercury vapor generators

In response to the environmental impact of mercury and the neuro-toxic risk associated with trophic transfer of methyl mercury to humans, the reduction of mercury emissions from coal-fired electric utilities, a significant anthropogenic source, is now receiving global attention. To address impending regulations for mercury reduction, there is a need to establish a mercury emissions measurement framework, which has demonstrated accuracy and traceability to national and international standards. To support this effort, the National Institute of Standards and Technology (NIST) has been working jointly with the United States Environmental Protection Agency (EPA) to develop a traceability system which links the output of elemental mercury calibration instrumentation sited at the power utilities, to the SI (International System of Units). This system is based on a reference (NIST Prime) elemental mercury generator standard, which is used by NIST to certify elemental mercury generators from the instrument vendors. These in turn are used by the instrument vendors to provide NIST traceable calibration for the instrumentation supplied to each electric utility. The NIST Prime generator is certified using a primary analytical method for the determination of mercury using sorbent trap analysis with isotope dilution cold-vapor inductively coupled plasma mass spectrometry (ID-CV-ICP-MS).

Micellar paclitaxel in the treatment of patients with tumors of the female reproductive system

Background. Treatment of patients with advanced cancers of the female reproductive system is very challenging. The most common treatment scheme for such patients includes paclitaxel 135—175 mg/m 2 + carboplatin AUC 5—6 or cisplatin 75 mg/m 2 . However, lengthy treatment with this regimen is limited by adverse events, such as neuropathy, allergic reactions, nephropathy, etc. The new micellar form of paclitaxel has demonstrated better tolerability compared to conventional paclitaxel and, considering the increased safe effective dose (up to 250 mg/m 2 ) it should ensure higher efficacy and better progression-free survival. The use of cremophor EL free paclitaxel is recommended in patients with concomitant extragenital diseases (including diabetes and neurological deficit), in elderly patients, and in patients with allergic reactions, as well as in cases when additional steroids should be avoided. Objective : to summarize the experience of using the new form of paclitaxel in patients with tumors of the female reproductive system and concomitant diseases. Materials and methods . We analyzed both world and our own experience in using micellar paclitaxel at a dose of200—250 mg/m 2 administered as a 1-hour intravenous infusion every 21 days for 3—6 treatment cycles in patients with solid tumors of the female reproductive system. Results. The polymeric micellar composition of cremophor EL free paclitaxel can be used in higher therapeutic doses with a lower risk of hypersensitivity and peripheral neurotoxicity. Fatigue and neuropathy were the most common dose-dependent adverse events of this drug. Nonew adverse reactions unknown for paclitaxel have been registered. Conclusions. The possibility of administration of micellar paclitaxel without premedication with steroids or at a minimum dose* makes it a promising candidate for further studies in combination with new targeted drugs and immunotherapy.

An Individualized Risk Mitigation Approach for Safety: Experience from the Mosunetuzumab (CD20/CD3 Bispecific Antibody) Development Program in Relation to Neurotoxicity Risk

An Individualized Risk Mitigation Approach for Safety: Experience from the Mosunetuzumab (CD20/CD3 Bispecific Antibody) Development Program in Relation to Neurotoxicity Risk

DDIS-30. EVALUATION OF THE SUSCEPTIBILITY OF NEURONS DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS TO ANTICANCER DRUGS FOR CNS TUMORS

Abstract Various chemical substances, including pharmaceuticals, pose potential risks of inducing acute or delayed neurotoxicity in adults and causing developmental neurotoxicity in fetuses or children. To ensure the safety of chemical substances and drugs, neurotoxicity risk assessment is critical, and an appropriate evaluation platform for neurotoxicity is desired. At present, several anticancer reagents, including temozolomide, cisplatin, and etoposide, are used for treatment of high-grade astrocytic tumors or medulloblastomas. In comparison to lots of information about anti-tumor cells effects of these reagents, their neurotoxicity to normal neurons, especially human derived cells, have been poorly investigated because of the low accessibility of human central nervous system (CNS) tissues, the technical difficulties related to neuron isolation from adult human CNS tissues, and the higher ethical controversy surrounding the use of human CNS tissues and/or fetal cells compared to animal tissues or cells. In this study, to overcome these issues, we made human induced pluripotent stem cells derived neurons (hiPSC-neurons) for preparing alternative assay for in vitro test using primary human neuronal cells, and evaluated their susceptibility to six commonly used anticancer drugs (temozolomide, nimustine, cisplatin, etoposide, mercaptopurine, and methotrexate). Human iPSC-neurons were differentiated using 5-week monolayer culture from hiPSC-derived neural stem/progenitor cells (hiPSC-NSPCs) established by combination the dual SMAD inhibition method with neurosphere culture. In vitro cytotoxic effects of six drugs on hiPSC-neurons and their parental hiPSC-NSPCs were evaluated by ATP assay and immunocytostaining. The hiPSC-neurons were generally more resistant to the anticancer drugs than hiPSC-NSPCs, although a high dose of cisplatin decreased the levels of the neuronal marker protein ELAVL3/4 in the hiPSC-neurons after a 48-h drug treatment. These results suggest that our methodology is potentially applicable for efficient determination of the toxicity of any drug to hiPSC-neurons.

Neuroprotection of miR-214 against isoflurane-induced neurotoxicity involves the PTEN/PI3K/Akt pathway in human neuroblastoma cell line SH-SY5Y

Isoflurane, one of the commonly used inhalation anesthetics worldwide in clinical practice, may generate substantial risks of neurotoxicity in the developing brains. The present study aimed to illustrate the effects and underlying mechanisms of miR-214 on isoflurane-induced neurotoxicity in human neuroblastoma cell line SH-SY5Y. SH-SY5Y cells were transfected with miR-214 or miR-con alone or in combination with pcDNA empty vector or pcDNA-PTEN in the presence of 3% isoflurane and incubated for 48 h. Cell viability, lactate dehydrogenase (LDH) release, apoptosis, and caspase-3/7 activity were evaluated using CCK-8, LDH release assay, flow cytometry analysis, and caspase-3/7 activity assay, respectively. The superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) activities were measured using commercial kits. miR-214 expression and alterations of the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway were detected by qRT-PCR and Western blot, respectively. The interaction between miR-214 and PTEN was explored by luciferase reporter assay. We found that isoflurane exposure induced neurotoxicity in SH-SY5Y cells, as evidenced by the reduced cell viability, increased LDH release, apoptotic rate, caspase-3/7 activity, and oxidative stress levels. Moreover, isoflurane exposure decreased the expression of miR-214 and affected the PTEN/PI3K/Akt pathway in SH-SY5Y cells. miR-214 overexpression significantly suppressed isoflurane-induced viability reduction, LDH release, apoptosis and oxidative stress, as well as inactivation of the PI3K/Akt pathway in SH-SY5Y cells. Interestingly, PTEN was identified as a target of miR-214. Moreover, PTEN upregulation blocked the effects of miR-214 on isoflurane-induced neurotoxicity in SH-SY5Y cells. In conclusion, miR-214 protected against isoflurane-induced neurotoxicity in SH-SY5Y cells via regulation of PI3K/Akt pathway by targeting PTEN, contributing to better understanding the underlying mechanisms of anesthetics-induce neurotoxicity.

2283. The Incidence and Risk Factors for Neurotoxicity in Patients on Ertapenem Therapy: a Retrospective Case- Control Study

BackgroundNumerous reports have emerged about the neurotoxic effects of ertapenem. A recent study supports carbapenem use for the treatment of extended spectrum β-lactamase (ESBL)- producing Gram-negative bacteremia. This will likely bolster the use of ertapenem as it is a convenient choice to complete antibiotic treatment in an outpatient setting. This study aims to review the incidence of neurotoxicity with ertapenem and the risk factors associated with it.MethodsA retrospective nested cohort study was conducted in Changi General Hospital in Singapore from January 2015 to Decemeber 2016. All patients who received at least 24 hours of ertapenem were identified. Those who exhibited ertapenem-associated neurotoxic effects were selected as cases while those who did not were included in the pool of controls and randomly selected at a 1:3 ratio.ResultsA total of 544 patients were treated with ertapenem in our hospital during this 2-year period. Twenty-five patients (incidence 4.6%) developed neurotoxic manifestations and 75 patients were included as controls. Acute confusion was the commonest reaction (n = 19, 76%) followed by hallucinations (n = 8, 32%) and seizures (n = 5, 20%). Baseline characteristics were similar in both groups; the median age of the cases was 79 years (IQR 71–83 years) and 14 (56%) were males. The median duration of ertapenem use before neurotoxicity occurred was 7 days (IQR 5–11days). The median Naranjo ADR probability score for cases was 7 (range 5 to 7) which suggests a probable relationship. Univariate analysis showed that renal impairment (with CrCl< 60 mL/minute) (OR 3.31, 95% CI 1.03–10.64), a history of a vulnerable brain (including stroke and epilepsy etc)(OR 2.61 95% CI 1.03–6.61) increased the risk of neurotoxicity. Neurotoxicity was also significantly associated with longer hospitalization (median 21 days, p = 0.03).ConclusionOur study suggests that renal impairment or a history of vulnerable brain may increase the risk for ertapenem-associated neurotoxicity. Hence, caution should be exercised when ertapenem is used to treat these individuals. Future prospective studies to further evaluate risk and to derive a prediction scoring system may help to reduce the incidence of neurotoxic adverse events with ertapenem use.Disclosures All authors: No reported disclosures.

The Chk1 inhibitor SAR-020106 sensitizes human glioblastoma cells to irradiation, to temozolomide, and to decitabine treatment

BackgroundGlioblastoma is the most common and aggressive brain tumour in adults with a median overall survival of only 14 months after standard therapy with radiation therapy (IR) and temozolomide (TMZ). In a novel multimodal treatment approach we combined the checkpoint kinase 1 (Chk1) inhibitor SAR-020106 (SAR), disrupting homologue recombination, with standard DNA damage inducers (IR, TMZ) and the epigenetic/cytotoxic drug decitabine (5-aza-2′-deoxycitidine, 5-aza-dC). Different in vitro glioblastoma models are monitored to evaluate if the impaired DNA damage repair may chemo/radiosensitize the tumour cells.MethodsHuman p53-mutated (p53-mut) and -wildtype (p53-wt) glioblastoma cell lines (p53-mut: LN405, T98G; p53-wt: A172, DBTRG) and primary glioblastoma cells (p53-mut: P0297; p53-wt: P0306) were treated with SAR combined with TMZ, 5-aza-dC, and/or IR and analysed for induction of apoptosis (AnnexinV and sub-G1 assay), cell cycle distribution (nuclear PI staining), DNA damage (alkaline comet or gH2A.X assay), proliferation inhibition (BrdU assay), reproductive survival (clonogenic assay), and potential tumour stem cells (nestinpos/GFAPneg fluorescence staining). Potential treatment-induced neurotoxicity was evaluated on nestin-positive neural progenitor cells in a murine entorhinal-hippocampal slice culture model.ResultsSAR showed radiosensitizing effects on the induction of apoptosis and on the reduction of long-term survival in p53-mut and p53-wt glioblastoma cell lines and primary cells. In p53-mut cells, this effect was accompanied by an abrogation of the IR-induced G2/M arrest and an enhancement of IR-induced DNA damage by SAR treatment. Also TMZ and 5-aza-dC acted radioadditively albeit to a lesser extent. The multimodal treatment achieved the most effective reduction of clonogenicity in all tested cell lines and did not affect the ratio of nestinpos/GFAPneg cells. No neurotoxic effects were detected when the number of nestin-positive neural progenitor cells remained unchanged after multimodal treatment.ConclusionThe Chk1 inhibitor SAR-020106 is a potent sensitizer for DNA damage-induced cell death in glioblastoma therapy strongly reducing clonogenicity of tumour cells. Selectively enhanced p53-mut cell death may provide stronger responses in tumours defective of non-homologous end joining (NHEJ). Our results suggest that a multimodal therapy involving DNA damage inducers and DNA repair inhibitors might be an effective anti-tumour strategy with a low risk of neurotoxicity.

In vivo efficacy of BCMA-iNKT-CAR is enhanced by NT-I7, a long-acting IL-7

B-cell maturation antigen (BCMA) targeted chimeric antigen receptor-T (CAR-T) cells generate short-lived responses in multiple myeloma (MM) with high risk of cytokine release syndrome and neurotoxicity. Expressing CAR proteins on alternative cell types could lead to a less toxic cure. Invariant natural killer T-cells (iNKTs) express a monomorphic T cell receptor that recognizes glycolipids displayed by the MHC-like molecule CD1d. iNKTs do not cause graft versus host disease (GvHD), making them a useful alternative cell type for an allogeneic,

P.271Potential translation of neurofilament light chain (NfL) as a safety biomarker for neurotoxicity in spinal muscular atrophy

Branaplam is an orally available small molecule that modulates Survival Motor Neuron 2 (SMN2) transcript splicing and increases generation of full length SMN2 mRNA with inclusion of Exon 7, leading to increased amount of functional SMN protein. It is in clinical development for treatment of Spinal Muscular Atrophy (SMA). Clear evidence of benefit has been shown without clinically apparent dose-limiting toxicities. However, non-clinical safety evaluations of branaplam suggested it may have a neurotoxicity risk. In toxicity studies using daily administration, a branaplam-related subtle peripheral neuropathy was discovered microscopically in juvenile dogs. This effect was potentially caused by stabilization ofmicrotubule polymerisation by branaplam. To investigate whether neurotoxicity is monitorable early, a thirty-week time-course study in dogs was conducted including digital nerve morphometry, measurement of neurofilament light (NfL) serum concentrations , and electrophysiological measurements. A minimal axonal degeneration of large fibers was confirmed at week 21. These findings correlated with release of NfL into serum. No clinical signs or changes in electrophysiological parameters were apparent, suggesting the microscopic findings and the associated serum increase of NfL precede neurologic dysfunction and overt clinical signs. Our data show that NfL is a sensitive marker of peripheral nerve injury and that it may be useful for monitoring the onset of treatment-related peripheral neurotoxicity in SMA patients and potentially, other indications. Differentiating between disease progression/activity and treatment-related adverse effects and understanding the relevance of increased NfL concentrations requires additional investigations. Although it remains unknown whether branaplam has a neurotoxic effect in humans, the weekly regimen used clinically may allow recovery from stabilizing effects on microtubule polymerization and avoid or minimize whatever led to the findings in dogs.

The CNS can be a safe space for CARs

In this issue of Blood, Frigault et al report that tisagenlecleucel, a CD19-specific chimeric antigen receptor (CAR) T-cell product, has a safety profile in a small series of patients with aggressive B-cell non-Hodgkin lymphomas (B-NHLs) and secondary central nervous system (CNS) involvement similar to that seen in patients without active CNS disease. 1 The Frigault et al study suggests that this product may benefit this previously excluded group of patients without an increased risk of neurotoxicity.

P14.73 Toxicity and outcomes of reduced-dose whole brain radiotherapy as consolidation treatment for patients with CNS lymphoma in real life setting

Abstract BACKGROUND Optimal treatment strategy for newly diagnosed primary PCNSL remains controversial. The high risk of radio-induced late-delayed neurotoxicity in patients who achieve long-term disease control constrains the use of classical consolidation WBRT. So as to reduce side cognitive effects, Morris et al, reported a phase II study, to assess the efficacy and toxicity of consolidation reduced-dose (23.4Gy) WBRT (rdWBRT) for patients with complete response after high dose methotrexate based chemotherapy. The study reported a 2-year PFS rate for these patients of 77%, with no evidence of significant cognitive decline during the follow-up (FU) period. The aim of this retrospective study was to report toxicity and outcomes of rdWBRT, in patients &lt; 60 years old with complete response (CR) after HD-MTX based chemotherapy, in real life setting, without selection bias. MATERIAL AND METHODS Patients were selected from the French LOC network database, a nationwide database centralizing since 2011 information from 28 different centers in France, representing the main centers involved in PCNSL management. Patients were retrospectively selected according to the following criteria: 1) Pathological diagnosis of diffuse large B cell PCNSL; 2) age&gt;18 and &lt;60 years; 3) immunocompetent status; 4) First line induction treatment based on high dose MTX (At least MTX&gt;1.5 g/m2); 5) CR according to the IPCG criteria after first-line induction treatment. Patients should have received a rdWBRT (23.4Gy in 13 fractions of 1.8Gy). RESULTS Twenty seven patients, were included. The median FU from initial diagnosis was 28.5 months [9.6–50.7]. Median age was 50.2 years [25–60]. Median Karnofsky Performans Status (KPS) was 90% [40–100%]. Seventeen patients had a multi focal disease at diagnosis (meningeal involvement n=6, in ophthalmic involvement n=4). PFS rates were 85% IC95[76–100 %], 65% IC95 [45–85%] and 65% IC95 [45–85%] at 1, 2, and 3 years respectively. The OS rates were 100%, 90,5% IC95 [77–100%] and 85%IC95 [69–100%]. 8 patients relapsed, with a median time from radiotherapy to recurrence of 6.5months [2.4–17]. All recurrences were outside the initially involved site(s), and 62.5% of tumors recurred as multifocal disease. All patients received salvage treatment, including intensive chemotherapy with autologous stem cell transplantation in 4 cases. No acute grade III-IV toxicity related to rdWBRT was reported. Neuropsychological follow up was available for 14 patients with no cognitive impairment at last follow up. CONCLUSION This is the largest retrospective study evaluating outcomes of rdWBRT for PCNSL young patients with CR after HD-MTX chemotherapy. Real life setting data from this study are quite reassuring, and rdWBRT could be considered as an efficient and safe consolidation strategy in this population. We need a longer FU to confirm the absence of cognitive deterioration.