Neurological Toxicity Research Articles

Shorter duration of Blinatumomab administration to 14 days has same efficacy and safety profile in treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia: A retrospective single‐center study

Introduction: Treatment of patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL) remains a significant clinical challenge. Many new strategies are changing the treatment landscape of r/r BCP-ALL in recent years. Blinatumomab has improved outcomes in r/r BCP-ALL, though high treatment costs and extended hospital stays are significant concerns. We considered that shortening the duration of blinatumomab administration during induction therapy might solve these problems. Methods: We retrospectively analyzed 19 patients with r/r BCP-ALL treated with different duration of blinatumomab, where 10 patients received blinatumomab for 14 days (Bli 14 D group) and 9 received it for a longer duration (LT group, 21-28 days). Results: The overall response rate (ORR) was 63.2% (12/19) of patients in total, and the ORR rates in 14 D and LT groups were almost the same (60% and 66.6%, respectively). The median overall survival (OS) was not reached in either groups. The median event-free survival (EFS) time was 4.1 months in LT group and not reached in D14 group. The most common adverse events were consistent with previous reports, including cytokine release syndrome (CRS), neurologic toxicity, and hematological toxicity. Conclusion: A 14-day blinatumomab administration may be a promising and well-tolerated regimen in r/r BCP-ALL, offering the same ORR and survival rates.

Cancer Therapy-Induced Encephalitis.

Encephalitis associated with cancer therapies is a rare but serious complication that can significantly impact patients' quality of life and it requires prompt identification and management. Over the past two decades, immunotherapy-particularly immune checkpoint inhibitors-has become a cornerstone of cancer treatment, with up to half of metastatic cancer patients in economically developed countries now receiving these therapies. The widespread adoption of immunotherapy has led to improved survival rates and long-term remissions, even in patients with advanced metastatic disease. However, as immune modulators, these therapies can trigger a range of immune-related adverse events, including a variety of novel neurological toxicities. Among these, encephalitis is of particular concern due to its potential severity, which can compromise treatment outcomes. This review aims to provide a comprehensive overview of the literature on this condition, highlighting optimal diagnostic strategies and management approaches to mitigate the risk of significant morbidity, while also comparing encephalitis induced by immunotherapy with that caused by traditional chemotherapies and targeted oncologic treatments.

FDA Approval Summary: Teclistamab - A Bispecific CD3 T-cell Engager for Patients with Relapsed or Refractory Multiple Myeloma.

On October 25, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to teclistamab-cqyv (TECVAYLI; Janssen Biotech) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. Substantial evidence of effectiveness was obtained from the MajesTEC-1 trial, a phase 1/2, single-arm, open-label, multi-center study. Patients received step-up doses of teclistamab at 0.06 mg/kg and 0.3 mg/kg followed by 1.5 mg/kg subcutaneously once weekly until disease progression or unacceptable toxicity. An overall response rate of 61.8% was observed, with a complete response or better rate of 28.2%. Cytokine release syndrome (CRS) occurred in 72% of patients and neurologic toxicity (NT) occurred in 57%, including immune effector cell-associated neurotoxicity syndrome (ICANS) in 6%. Due to the risk of CRS and NT, including ICANS, the U.S. prescribing information for teclistamab includes a boxed warning and teclistamab is available only through a restricted program under a risk evaluation and mitigation strategy. Here, we summarize the data and FDA review supporting the accelerated approval of teclistamab, a BCMA-directed bispecific antibody that was the first bispecific CD3 T-cell engager approved for treatment of multiple myeloma.

Multi-omics inhalation toxicity assessment of urban soil dusts contaminated by multiple legacy sources of lead (Pb)

Although animal studies have evaluated lead (Pb) toxicity, they are limited to soluble forms, such as Pb-acetate, which do not reflect the range found in the exposome. Recent studies on Pb speciation of residential soils in urban areas revealed that the initial Pb sources are not persistent and are extensively repartitioned into adsorbed forms of Pb rather than insoluble phosphates. We investigated the inhalation and neurological toxicity of dusts generated from a surficial soil sample collected from a residential site with an exposomic mixture of various Pb species, both adsorbed phases (Fe and Mn oxide, humate bound Pb) and mineral phases (Pb hydroxycarbonate, pyromorphite, galena). Mice inhaled East Chicago dust (ECD) generated from a composite soil sample for 4 h/day, 7 days/week, for 4 weeks. Mice were necropsied immediately, 1, 14 and 30 days post exposure to evaluate both toxicity and recovery. Exposure to ECD caused changes in memory and spatial learning in the Morris Water Maze test. RNAseq analysis of the hippocampus region revealed multiple differentially expressed genes and impacts on pathways involved in ion channel complexes, and neuron-to-neuron synapse. Metabolomics analysis of plasma highlighted significant alterations in metabolic processes immediately after exposure that resolved after 14 days of rest.

Comparative Evaluation of Aminoguanidine, Semicarbazide and Thiosemicarbazide Treatment for Methylglyoxal-Induced Neurological Toxicity in Experimental Models

Background: Advanced glycation end products (AGEs) are complex compounds that play a critical role in neurological disorders, including the pathogenesis of Alzheimer's disease. Methylglyoxal (MG) is recognized as the primary precursor of AGEs. Methylglyoxal is produced endogenously and also introduced through dietary exposures. Objectives: This study aimed to investigate and compare the effects of aminoguanidine (AG), semicarbazide (SC), and thiosemicarbazide (TSC) on MG-induced neurological toxicity in rats. Methods: Male Wistar rats were exposed orally to MG, MG + AG, MG + SC, and MG + TSC for 70 days. Neurobehavioral, biochemical, and histopathological changes were evaluated. Results: The findings indicated that oral administration of MG for 70 days resulted in memory impairment and increased anxiety in neurobehavioral tests. Additionally, MG elevated protein carbonylation in brain tissues. Semicarbazide was found to prevent MG-induced memory problems, while both SC and AG reduced carbonyl content in brain tissues. Advanced glycation and TSC were effective in alleviating anxiety induced by MG exposure. Histopathological analysis revealed that MG caused cell damage and neuronal necrosis in the hippocampus, particularly in the cornu ammonis 1 (CA1) and dentate gyrus (DG) regions. However, AG, SC, and TSC improved neuronal survival in these areas. Conclusions: The data suggest that SC, AG, and TSC may offer neuroprotective effects against MG-induced neurobehavioral toxicity. Further studies are required to explore the mechanisms of action of these compounds.

B-221 Combined RT-PCR and Whole Exome Sequencing Pharmacogenetic Testing in Polypharmacy Patient: A Case Report

Abstract Background Pharmacogenetics has become one of the main branches of Precision Medicine owing to its usefulness for patients’s optimal therapeutic management. Notwithstanding, pharmacogenetic testing results must be taken carefully, specially in multimorbidity patients with a variety of drugs prescribed. The aim of the present work is to introduce a combined RT-PCR and Whole Exome Sequencing Approach for pharmacogenetic testing in a patient with multiple drug-related adverse events. Case Background A 67 years old female was derived to our Clinical Chemistry Unit for pharmacogenetic testing due to multiple drug-related adverse events: nifedipine-voriconazole interaction, voriconazole-related neurological toxicity and moxifloxacin-related dizziness. Aditionally, she had been receiving morphine, corticoid for her reumatoid arthritis and antituberculous therapy (r isoniazid / pyrazinamide / rifampin and ethambutol). Methods Patient’s DNA was extracted from a blood sample and undergone by pharmacogenetic testing in two parallel ways: -A first genotyping assay was carried out using Taqman® OpenArray™ PGx Express 120 panel (ThermoFisher™), according to manufacturer’s instructions. -Simultaneusly, in order to cover possible copy number variants and SNPs not covered by our RT-PCR array, a whole exome sequencing run was performed on IlluminaTM NextSeq 1000. Sample library was prepared applying a custom GRCh38 pipeline. Results Relevant variants related to patient’s therapy found by RT-PCR are shown in table 1. SNPs genotyped by RT-PCR were confirmed by NGS. Moreover, whole exome sequencing revealed a deletion in exon 5 of SLCO1B1 gene, which corresponds to SLCO1B1*49 (loss of function); and some variants in NAT2 that may cause toxicity in antituberculous treatment (diplotype NAT2*6C/*7C). Conclusions In those challenging cases that involve multimorbidity and polypharmacy patients, pharmacogenetic testing must be approached taking into account variants that are not covered by the analytical method routinely used and the possibility of complement it with alternative proccedures.

Pediatric Charcot-Marie-Tooth disease and peripheral nerve blocks:a retrospective cohort study of 25 patients.

Charcot-Marie-Tooth (CMT) disease is an inherited neurologic disorder characterized by progressive peripheral neuropathies. The use of peripheral nerve blocks (PNB) in patients with CMT disease has been controversial because of concerns about exacerbating existing neurologic impairments and the "double hit" hypothesis. We aimed to assess the use of PNB in pediatric patients with CMT disease undergoing orthopedic surgery to address the limited data available in the literature on this topic. In this retrospective cohort study, we included all pediatric patients with CMT disease scheduled for orthopedic surgery receiving PNB at our centre. All of the patients had preoperative neurologic exams and received one or more ultrasound-guided regional anesthesia techniques. Data extracted included details of anesthesia technique, surgical procedure, opioid consumption, and pain scores during the first three postoperative days. We also reviewed any complications such as neurologic deficits and local anesthetic toxicity. We used descriptive statistics to summarize the findings. We included 25 patients, 14 of whom (56%) presented with pre-existing neurologic deficits, primarily in the lower extremities. Postoperative assessments revealed no new neurologic impairments in 24/25 (96%) patients, with only one patient experiencing a nerve injury possibly related to the surgical procedure. Opioid consumption was low in the postanesthesia care unit and on the day of surgery. No additional complications were noted in the first 72hr after surgery. Despite concerns, PNB showed favourable outcomes in a pediatric cohort with CMT disease, with low opioid consumption and pain scores and minimal complications during follow-up. These findings match previous reports of adult patients with CMT disease and suggest that the benefits of PNB may outweigh the perceived risks in pediatric patients with CMT disease.

Effects and Toxicity of Hallucinogenic New Psychoactive Substances From the Perspectives of e-Psychonauts

Hallucinogenic new psychoactive substances have been rapidly emerging due to the increasing use of the Internet as a marketplace and source of information. This study explores hallucinogenic new psychoactive substances’ profile, effects and toxicity from the perspectives of e-psychonauts by conducting content analysis of online discussion forums. Qualitative content analysis was applied to threads extracted from online discussion forums. Each thread was coded carefully, and similar codes were grouped into sub-themes and themes respectively. The results showed four main themes related to users’ characteristics, hallucinogenic new psychoactive substances profile, effects and toxicity. The majority of users in this study were men in the age range of 18–25 years old. The main effects sought were stimulant/hallucinogenic effects; yet neurological and cardiovascular toxicity were frequently reported. The research found that online discussion forums offered a rich source of information as they provided a safe space for truthful experience reports without fear of legal consequence for e-psychonauts.

Heat stress sensitizes zebrafish embryos to neurological and cardiac toxicity

Global warming increases the risk of dangerous heat waves, which may have deleterious effects on humans and wildlife. Here, we have utilized zebrafish embryos as a model to analyze heat stress and effect of chemical compounds on responses to heat stress. The temperature adaptation limit of zebrafish embryos was 37 °C in behavioural test and 38 °C in cardiac test. Polyaromatic hydrocarbon phenanthrene completely blocked the behavioural adaptation to heat stress. Interestingly, the cardiotoxic effects of lapatinib, phenanthrene and paclitaxel were induced by heat stress. Taken together, our data indicates that motility and cardiac function of zebrafish embryos can be utilized as a model to analyze modulatory effects of compounds on heat stress.

Metabolomic Prediction of Breast Cancer Treatment-Induced Neurologic and Metabolic Toxicities.

Long-term treatment-related toxicities, such as neurologic and metabolic toxicities, are major issues in breast cancer. We investigated the interest of metabolomic profiling to predict toxicities. Untargeted high-resolution metabolomic profiles of 992 patients with estrogen receptor (ER)+/HER2- breast cancer from the prospective CANTO cohort were acquired (n = 1935 metabolites). A residual-based modeling strategy with discovery and validation cohorts was used to benchmark machine learning algorithms, taking into account confounding variables. Adaptive Least Absolute Shrinkage and Selection (adaptive LASSO) has a good predictive performance, has limited optimism bias, and allows the selection of metabolites of interest for future translational research. The addition of low-frequency metabolites and nonannotated metabolites increases the predictive power. Metabolomics adds extra performance to clinical variables to predict various neurologic and metabolic toxicity profiles. Untargeted high-resolution metabolomics allows better toxicity prediction by considering environmental exposure, metabolites linked to microbiota, and low-frequency metabolites.

The potential role of CAR-T in Multiple Myeloma Treatment. A review

Background: Multiple myeloma (MM) is a hematologic malignancy, which causes accumulation of plasma cells in the bone marrow. The symptoms of MM are associated with organ dysfunction and include hypercalcemia, renal failure, anaemia and bone destruction. A relatively new and promising therapeutic option for MM is CAR-T therapy. Aim of the study: The study aimed to outline the role of CAR-T therapy in MM treatment.Material and methods: We conducted a literature review containing 24 articles. We described the role of CAR-T in MM therapy, its therapeutic points, the effectiveness of therapy, and its side effects.Results: CAR-T cells transduced with CAR can recognize specific antigens and kill the cancer cells. For MM these specific antigens are integrin β7, SLAMF7, CD138, BCMA, GPRC5D and FCRL5. Integrin β7 in its active form, can be found in MM cells, whereas in other blood cells, integrin β7 is in the inactive form. The expression of SLAMF7 on MM cells is high and uniform, but its function is not clear: expression of SLAMF7 in MM is suspected to increase the survival and adhesion of MM cells to bone marrow stromal cells. CD138's strong expression on MM cells is contributing to their development and proliferation. BCMA expression was not detected in other human tissues, only in MM cells. GPRC5D is highly expressed in bone marrow samples from MM patients, and minimally expressed in other hematologic malignancies. FCRL5 is a protein marker found specifically on plasma cells in MM, its increased expression promotes B cell proliferation. The AlloCAR-T therapy also seems to be an effective method.CAR-T therapy has also adverse effects including cytokine release syndrome, neurological toxicity, haematological disorders and infusion fever. Conclusions: The effects of CAR-T therapy in MM are really promising and give real benefits to patients. For this reason, it should be further developed and subjected to further research.

Neuronal toxicity of monoclonal antibodies (mAbs): an analysis of post-marketing reports from FDA Adverse Event Reporting System (FAERS) safety database.

Monoclonal antibodies (mAbs) are pivotal in treating various diseases, including cancers and autoimmune disorders. Despite their therapeutic benefits, mAb therapy has been associated with neurological toxicity. This study aimed to assess the occurrence of neuronal toxicity associated with mAbs, utilizing data from the FDA Adverse Event Reporting System (FAERS) safety database. The study also sought to delineate the medical characteristics of the reported cases. A comprehensive analysis of neurological adverse events reported in the FAERS database was conducted, employing computational methodologies such as proportional relative risk (PRR), information component (IC025), and chi-square (χ2). Individual case safety reports (ICSRs) pertaining to neurological disorders linked to mAbs from the date of first global marketing authorization until June 30, 2023, were meticulously examined. The FAERS safety database contains 79,022 ICSRs linking mAbs to nervous system disorders. Rituximab, bevacizumab, denosumab, nivolumab, and trastuzumab were frequently cited. Reported adverse events include headache, peripheral neuropathy, dizziness, and cerebrovascular accident. Most ICSRs (85.81%) were serious, mainly affecting females (57.04%) with a 14.09% fatality rate. Panitumumab, atezolizumab, bevacizumab, and trastuzumab showed strong drug-event associations. Signal disproportionate reporting (SDR) analysis flagged myasthenia gravis, peripheral neuropathy, and neurotoxicity across multiple mAbs, suggesting potential signals. Interdisciplinary collaboration between oncologists and neurologists is crucial for safe mAb use. Our study enhances understanding of mAb neurological safety. Disproportionality signal analysis provides valuable evidence for risk mitigation.

CAR T-cells therapy as a ray of hope for cancer treatment

New hope for patients with specific blood malignancies has arisen with the emergence of chimeric antigen receptor (CAR) T-cell therapy as a revolutionary approach to cancer immunotherapy. This groundbreaking therapy modifies a patient’s immune system such that their own T cells can identify and destroy cancer-specific antigens by expressing CARs. Multiple myeloma, lymphomas, and leukemias are among the blood malignancies that have been treated with six CAR T-cell treatments that have been approved by the FDA since 2017. The treatment entails drawing T cells out of the patient’s blood, changing their genes to produce CARs, and then reintroducing these modified cells into the patient. The CAR T-cells have the ability to identify cancer cells, proliferate, and kill them once they enter the circulation. This might lead to long-term protection from the illness. Patients with blood malignancies who have relapsed or are resistant to previous treatments have shown encouraging results in clinical studies, with some patients even managing to achieve long-term remissions. Cytokine release syndrome and neurological toxicities are two of the many potential adverse effects of CAR T-cell treatment that must be carefully managed. The complicated production method and expensive treatment cost further restrict its broad availability. Research is ongoing with the goals of improving the safety profile, increasing the effectiveness, and expanding the applicability of CAR T-cell therapy to solid tumors.

Prospecting the anti-inflammatory potential and analysis of the neurological interaction and toxicity of compounds present in the fruits Persea americana (Avocado), Mangifera indica (Mango) and Hancornia speciosa (Mangaba)

Prospecting the anti-inflammatory potential and analysis of the neurological interaction and toxicity of compounds present in the fruits Persea americana (Avocado), Mangifera indica (Mango) and Hancornia speciosa (Mangaba)

S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine for the treatment of non-small cell lung cancer through regulating NF-κB signalling pathway without neurotoxicity

The discovery of novel targeted agents for non-small cell lung cancer (NSCLC) remains an important research landscape due to the limited efficacy, side effects and drug resistance of current treatment options. Among many repurposed drugs, disulphiram (DSF) has shown the potential to target tumours. However, its unpleasant neurotoxicity greatly limits its use. A DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine (DS-NAC), was synthesised against NSCLC. The therapeutic effects, mechanism and toxicities of DS-NAC were evaluated in A549 and H460 cells and the mouse model of in situ lung cancer. The in vitro results exhibited that DS-NAC had potent anti-proliferation, apoptotic, anti-metastasis and epithelial–mesenchymal transition (EMT) inhibition effects. In the orthotopic lung cancer mouse model, therapeutic effects of DS-NAC were better than those of DSF and were similar to docetaxel (DTX). Also, results from western blot and immunohistochemistry showed that DS-NAC in combination with copper exerted therapeutic effects via regulating NF-κB signalling pathway and ROS-related proteins such as HIF-1α, Nrf2 and PKC-δ rather than regulating ROS level directly. Moreover, the safety evaluation study showed that DS-NAC had low haematologic and hepatic toxicities in comparison with DTX as well as low neurological toxicity compared with DSF. DS-NAC could be a promising anti-lung cancer agent with a favourable safety profile.

Crystal structure of a tetrameric RNA G-quadruplex formed by hexanucleotide repeat expansions of C9orf72 in ALS/FTD.

The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex composed of two four-layer dimeric G-quadruplex via 5'-to-5' stacking in coordination with a K+ ion. Notably, the two C bases locate at 3'- end stack on the outer G-tetrad with the assistance of two additional K+ ions. The high-resolution structure reported here lays a foundation in understanding the mechanism of neurological toxicity of RNA HREs. Furthermore, the atomic details provide a structural basis for the development of potential therapeutic agents against the fatal neurodegenerative diseases ALS/FTD.

Multi-institutional study of reirradiation for recurrent high grade glioma.

2063 Background: Treatment options are limited for recurrent WHO Grade 3-4 glioma (HGG). Reirradiation (ReRT) is an option, but the ideal treatment regimen and the benefit of concurrent and adjuvant systemic therapy in the recurrent setting remains unclear. Methods: A retrospective review of patients with recurrent HGG treated with reRT was conducted at 12 institutions. Eligible patients were treated with two courses of fractionated RT (>3 fractions) for glioma with the second course being for HGG. To estimate overall and progression free survival times, the Kaplan-Meier method was used. To assess the relationship between survival times and study variables, Cox proportional hazard regression models were used to calculate hazard ratios and the corresponding 95% confidence interval along with the p-value. SAS (version 9.4, Cary, NC, USA) was used for all analyses. P values < 0.05 were assumed to be statistically significant. Results: 482 eligible patients were identified from 1997 to 2023. 235 (54%) had histologic confirmation of glioblastoma at reRT. The median age at reRT was 53.1 years and median KPS was 80. 196 patients (51%) were treated with reRT at their initial recurrence and 122 (30%) had an IDH mutation. The most common reRT dose and number of fractions were 35 Gy and 10 fractions. 192 patients (44%) and 95 (24%) received concurrent (conc) and adjuvant (adj) temozolomide (TMZ) respectively and 116 (27%) and 110 (28%) received conc and adj bevacizumab (BEV) respectively with reRT. Median OS and PFS were 9.8 and 5.3 months. OS (16.6 vs 7.8 months, HR 2.44 p < 0.01) and PFS (8.6 vs 4.6 months, HR 1.85 p < 0.01) were longer in patients with IDH mutations. Receipt of conc and adj TMZ with reRT was associated with improved OS (HR 0.67 p < 0.01 and HR 0.49 p < 0.01 respectively) and PFS (HR 0.66 p <0.01 and HR 0.47 p < 0.01 respectively). Receipt of concBEV with reRT was associated with worse OS (HR 1.66 p < 0.01) but not PFS (HR 1.15 p = 0.28). AdjBEV was not associated with OS or PFS. Concurrent and adjTMZ were associated with improved OS ( p = 0.04 and <0.01) and PFS ( p = 0.01 and <0.01) for IDHwt tumors. In IDHmt tumors, concTMZ was associated with improved OS but not PFS ( p = 0.03 and 0.11), while adjTMZ was associated with improved OS and PFS ( p = 0.05 and <0.01). Symptomatic adverse radiation effects and Grade 3 or greater neurologic toxicity were seen in 107 (25%) and 86 (20%) of patients respectively. Neither conc nor adjBEV nor TMZ were associated with symptomatic ARE. ConcBEV was associated with lower (13% vs 23%, p = 0.03) and concTMZ was associated with higher rates (25% vs 15%, p = 0.01) of Grade 3 or greater neurologic toxicity. Conclusions: The use of concurrent and adjuvant TMZ with reRT are associated with improved OS and PFS in recurrent HGG. OS and PFS are improved with conc and adjTMZ for IDHwt tumors, while there was no PFS benefit to concTMZ in IDHmt tumors. The rate of high grade neurologic toxicity was decreased with the use of concurrent BEV and increased with the use of concTMZ.

Examining the risk of immune checkpoint inhibitor-related toxicity among patients with melanoma and their history of cannabis use.

e21539 Background: With cannabis use rising due to better availability for recreational and medicinal uses, there is a need for studies examining cannabinoids interactions. Immune Checkpoint Inhibitors have been increasing in popularity among metastatic cancer patients like those with melanoma. The biological impact of cannabis is mediated in part by the CB1 and CB2 receptors present in the endocannabinoid system that is present in the immune system. ICI therapy also targets the immune system through manipulating PD-1/PD-L1 receptors to induce cancer cell death. Therefore, concurrent cannabis use with ICI therapy could have potentiating effects on toxicities and negatively impact efficacy. There is limited information in the literature examining this and therefore the goal was to examine the impact of ICI toxicity risk among melanoma patients on any form of ICI therapy. Methods: A retrospective cohort study was conducted using TriNetX, a multicenter database comprised of ~100 million patients across 84 healthcare organizations. Adults ( > 17 years) from 2012-2023 were identified based on ICI-therapy initiation within 1 month of malignant melanoma diagnosis. Patients were then stratified by history of those with and without cannabis use disorder. ICI toxicity categories were determined a priori and included cardiac, nephrological, gastrointestinal, endocrine, respiratory, ocular, hematological, hepatological, musculoskeletal, and neurological toxicities. 1:1 propensity score matching was conducted to control for comorbidities and demographics. Adjusted hazard ratios (aHR) with 95% CI were calculated at 1-year follow-up after therapy initiation for ICI toxicities between the cohorts. aHR was estimated using the Cox proportional hazard model. Results: A total 14589 melanoma patients who underwent ICI therapy were identified where 2.3% had history of cannabis use. Matching revealed two balanced cohorts of 344 patients. Melanoma patients with a history of cannabis use did not have any significant differences with controls for cardiotoxicity (aHR[95%CI] = 0.94[0.54,1.6]), Nephrotoxicity (0.86[0.51,1.5]), GI toxicity (1.44[0.95,2.2]), endocrine toxicity (1.2[0.82,1.8]), respiratory toxicity (0.93[0.55,1.6]), ocular toxicity (0.63[0.25,1.6]), hematologic toxicity (1.04[0.7,1.6]), neurotoxicity (1.04[0.6,1.7]), liver toxicity (1.41[0.78,2.5]), or musculoskeletal toxicity (1.53[0.62,3.8]). Conclusions: With cannabis use rising due in part to recreational use and in part to medical marijuana, the implications of use must be a topic of research. Cannabis use among melanoma patients did not provide any significant differences in risk of developing ICI-therapy-related toxicities. Additional studies are needed to validate this finding.

Factors derived from human exfoliated deciduous teeth stem cells reverse neurological deficits in a zebrafish model of Parkinson's disease

Background/purposeMesenchymal stem cells exhibit therapeutic efficacy for brain injury. This study examined the effect of mesenchymal stem cells derived from human exfoliated deciduous teeth (SHED) on alleviating symptoms of Parkinson's disease (PD). Materials and methodsSHED were isolated to examine the biosafety and bioavailability of stem cells derived from human exfoliated deciduous teeth-derived conditioned medium (SHED-CM) for the alleviation of PD symptoms in a 6-hydroxydopamine (6-OHDA)-induced PD zebrafish model. ResultsSHED-CM administration did not induce neurological, skin or muscle toxicity in control zebrafish at any dose, and estrogen equivalent testing showed no chronic toxicants. Induction of PD with 6-OHDA suppressed zebra SHED-CM was administered to zebrafish treated with 6-OHDA to induce PD symptoms. Similar to nomifensine, a drug with proven anti-PD potential, SHED-CM repaired the motor deficiencies in the zebrafish PD model. ConclusionOur results indicate the biosafety of SHED-CM and its therapeutic potential in treating PD in a zebrafish model.

Targeted interventions to address local challenges in HR+/HER2- and HER2+ breast cancer treatment in community-based settings.

e23213 Background: Advancements in novel targeted agents and antibody-drug conjugates (ADCs) have dramatically improved patient outcomes and survival for breast cancer patients, yet the successful utilization of these agents remains a key challenge for clinicians, particularly in the community. To improve the care of HR+/HER2- and HER2+ patients, a quality improvement (QI) initiative was conducted across 6 community-based oncology practices. Methods: Between 7/2023 and 10/2023, multidisciplinary oncology team members (N = 98) across 6 US-based community oncology practices were surveyed to identify gaps in the treatment and management of patients with HR+/HER2- and HER2+ breast cancer. Providers then participated in audit/feedback (AF) sessions where they (a) assessed site-specific practice gaps identified via the provider surveys; (b) received targeted education based on their specific gaps; and (c) developed action plans for improvement. Follow-up surveys administered 90 days after AF sessions will evaluate the impact of practice changes driven by the QI initiative. Results: Top challenges reported by providers in caring for patients with HR+/HER2- and HER2+ breast cancer were providing patient-centered supportive care measures (37%), individualizing treatment plans (18%), and managing treatment-related adverse events (14%). Reported challenges in treatment sequencing included rapidly evolving guideline recommendations (44%) and knowing which treatment to select when patients are eligible for multiple lines of therapy (34%). Additionally, oncology team members reported having the most difficulty managing treatment-related neurological effects (32%), neutropenia (16%), and GI toxicities (14%). Providers believed improved collaboration across interprofessional teams (28%) and increased patient education/referrals for supportive care (26%) would most improve care for breast cancer patients. To address the identified gaps at each location, teams participated in targeted AF sessions focused on addressing their specific gaps and developed action plans, such as developing new workflows for improving care coordination, implementing institutional protocols for identifying and managing adverse events, and improving patient supportive care, quality-of-life assessments, and distress screenings. Full findings from baseline surveys will be presented, along with follow-up surveys measuring real-world impact of the system-level practice changes. Conclusions: Through this QI initiative, teams identified gaps/barriers in their own practices, and developed and implemented action plans for improvement. These data and actionable insights support safe, effective, and evidence-based integration of novel therapies into HR+/HER2- and HER2+ breast cancer care to optimize patient outcomes.