Ototoxic Effects Research Articles

Cisplatin vestibulotoxicity: a current review.

Cisplatin, a commonly used chemotherapy drug, is well-established for its ototoxic effects, primarily attributed to the damage it inflicts on cochlear hair cells. However, its impact on the vestibular system remains inadequately understood. Here, we provide a comprehensive review of existing literature concerning cisplatin-induced vestibulotoxicity. Animal studies have shown that cisplatin induces a vestibular hair cell loss that is dose-dependent, with the severity of damage also varying according to the route of administration. Notably, intratympanic and systemic injections in animal models have manifested significant damage primarily to utricular hair cells, with a lesser degree of damage observed for the other vestibular end organs. The underlying mechanisms of cisplatin induced vestibular hair cell loss include apoptosis, oxidative stress, and inflammatory cytokines. Several protective agents, such as Pifithrin-α, DAPT, Ginkgolide B, and heat shock proteins, have demonstrated efficacy in inhibiting cisplatin-induced vestibular damage in preclinical studies. Human clinical findings indicate that cisplatin treatment can cause vestibular dysfunction, characterized by symptoms ranging from transient dizziness to persistent vertigo. Challenges in diagnosis, including the limited utilization of comprehensive vestibular testing for many patients, contribute to the variability in reported outcomes. Cisplatin-induced vestibulotoxicity is a significant complication of chemotherapy, necessitating further research to understand its mechanisms and to improve diagnosis and management, ultimately aiming to enhance the quality of life for cancer patients undergoing cisplatin therapy.

Strengthening cancer care through the inclusion of audiological services

Aim Commonly used cancer treatments that treat the priority cancers are ototoxic. Ototoxicity can add to the already severe morbidity experienced by cancer survivors. It affects the quality of life and consequently has dire psycho-socio-emotional, cognitive, occupational, and scholastic effects. This article aims to highlight that the inclusion of audiological services, such as ototoxicity monitoring and management, can strengthen cancer care by reducing the morbidity and effects of ototoxicity. It explores the current practices of ototoxicity monitoring and management for cancer patients in South Africa and offers practical and innovative evidence-based solutions on how the practice can be improved. The paper also discusses how the National Care Strategic Framework (NCSF) (2017-2022) can be expanded to support the inclusion of audiological services by including ototoxicity monitoring and management in cancer care. Methods A review of literature was conducted utilising a narrative approach to explore audiological service provision for cancer care in South Africa. Peer-reviewed publications and clinical guidelines related to audiological and/or vestibular ototoxicity caused by cancer treatments were reviewed. Findings Despite the inroads that have been made in South Africa, resource and logistical limitations hinder the effectiveness of ototoxicity monitoring and management programmes. In addition, a lack of awareness of the ototoxic effects of some cancer treatments by oncology nurses, as well as ambiguity regarding the roles and responsibilities of the multidisciplinary cancer team in terms of ototoxicity monitoring, management, and patient counselling, further exacerbate the problem. Conclusions The effectiveness of ototoxicity monitoring and management could be enhanced by having a national and standardised protocol and programme incorporating tele-audiology and task-shifting. In addition, collaborative work among the cancer multidisciplinary team will foster holistic practice and integration of audiological services. Future versions of the NCSF should encompass considerations to reduce the associated burdens of cancer treatment, and audiological services, through ototoxicity monitoring, and ought to be included when providing cancer care to patients being treated with ototoxic agents.

Protective Effects of Gastrodin Against Gentamicin-Induced Vestibular Damage by the Notch Signaling Pathway.

Gentamicin is a broad-spectrum antibiotic commonly used in clinical practice. However, the drug causes side effects of ototoxicity, leading to disruption in balance functionality. This study investigated the effect of gastrodin, a prominent compound present in Gastrodia, and the underlying mechanism on the development of gentamicin-induced vestibular dysfunction. Wild-type C57BL/6 mice were randomly assigned to three groups: control, gentamicin, and gentamicin + gastrodin groups. The extent of gentamicin-induced vestibular impairment was assessed through a series of tests including the swimming test, contact righting reflex test, and air-righting reflex. Alterations in vestibular hair cells were monitored through immunofluorescence assay, and cellular apoptosis was observed using TUNEL staining. The mRNA and protein expression of Notch1, Jagged1, and Hes1 was quantified through qRT-PCR, immunofluorescence, and western blot analyses. Gentamicin treatment led to pronounced deficits in vestibular function and otolith organ hair cells in mice. Nevertheless, pretreatment with gastrodin significantly alleviated these impairments. Additionally, the Notch signaling pathway was activated by gentamicin in the utricle, contributing to a notable increase in the expression levels of apoptosis-associated proteins. By contrast, gastrodin treatment effectively suppressed the Notch signaling pathway, thereby mitigating the occurrence of apoptosis. Collectively, these findings underscore the crucial role of gastrodin in safeguarding against gentamicin-induced vestibular dysfunction through the modulation of the Notch signaling pathway. This study suggests the potential of gastrodin as a promising therapeutic agent for preventing vestibular injuries.

Apoptosis, autophagy, ferroptosis, and pyroptosis in cisplatin-induced ototoxicity and protective agents.

Cisplatin is widely used to treat various solid tumors. However, its toxicity to normal tissues limits its clinical application, particularly due to its ototoxic effects, which can result in hearing loss in patients undergoing chemotherapy. While significant progress has been made in preclinical studies to elucidate the cellular and molecular mechanisms underlying cisplatin-induced ototoxicity (CIO), the precise mechanisms remain unclear. Moreover, the optimal protective agent for preventing or mitigating cisplatin-induced ototoxicity has yet to be identified. This review summarizes the current understanding of the roles of apoptosis, autophagy, ferroptosis, pyroptosis, and protective agents in cisplatin-induced ototoxicity. A deeper understanding of these cell death mechanisms in the inner ear, along with the protective agents, could facilitate the translation of these agents into clinical therapeutics, help identify new therapeutic targets, and provide novel strategies for cisplatin-based cancer treatment.

Which Environmental Pollutants Are Toxic to Our Ears?-Evidence of the Ototoxicity of Common Substances.

Ototoxicity refers to the adverse effects of substances on auditory or vestibular functions. This study examines the evidence of ototoxicity's association with exposure to common environmental pollutants, as documented in toxicological profiles by the Agency for Toxic Substances and Disease Registry. Our aim was to evaluate whether the evidence supports modifying the charting of ototoxic effects in the summary tables of these toxicological profiles and providing a guide for scientists to access these data. Health outcomes of interest included hearing loss, vestibular effects, cochlear lesions, tonal alterations, cellular damage, and ototoxicity-related outcomes (neurological, nephrotoxic, hepatic, and developmental effects). We obtained ototoxicity information for 62 substances. Hearing-related effects were reported, along with neurological effects. Overall, 26 profiles reported strong evidence of ototoxicity, including 13 substances previously designated as ototoxic by other health and safety agencies. Commonly studied outcomes included hearing loss, damage to ear anatomy, and auditory dysfunction. Vestibular dysfunction and tinnitus are rarely studied. Our findings highlight the lack of conclusive evidence of ototoxic properties for many substances, especially for pesticides and herbicides. This review supports charting the evidence of ototoxicity separately in toxicological profiles' summary tables. Improving the communication of ototoxicity-related health effects might impact their recognition and prompt further research. A stronger evidence base could support improved prevention efforts in terms of serious health outcomes.

Unveiling the ototoxic effects of paraquat on zebrafish larva

Paraquat is a widely utilized herbicide in agricultural fields posing a significant impact on human health and the environment due to its potent oxidant properties. Rampant paraquat usage leads to serious health hazards to farmers and the ecosystem, particularly the water bodies. Paraquat exposure can damage dopaminergic neurons causing Parkinson's disease in humans and other animal models. Extensive research has been done regarding the mode of action, pathophysiology and molecular mechanisms of paraquat-induced Parkinson's disease. Meanwhile, the ototoxic effect of paraquat remains poorly understood. Potential ototoxins can cause sensorineural hearing loss, one of the most common sensory disabilities in humans. In this study, we investigated the harmful effects of paraquat on neuromast hair cells in zebrafish larvae, a powerful model organism for auditory research. We treated sub-lethal concentrations (125 μM to 1000 μM) of paraquat to 3 and 4 dpf zebrafish larvae to investigate its ototoxic effects via rheotaxis behavioral assay, neuromast staining and scanning electron microscopy. The behavioral assay findings showed a drastic decline in the rheotaxis behavior in all the concentrations of paraquat-treated larvae. Furthermore, DASPEI neuromast vital staining displayed a dose-dependent reduction in the neuromast hair cells as we increased the paraquat concentration. The scanning electron microscope data revealed the significant shortening of kinociliary length, a decrease in stereociliary density and changes in semilunar peridermal cell morphology signifying the damaging effects of paraquat at the cellular level. Collectively, the behavioral, anatomical and morphological studies highlight the potential ototoxic effects of paraquat on zebrafish neuromast hair cells, further signifying its potential role in causing hearing loss in humans.

One mechanism of sudden sensorineural hearing loss after sildenafil and sexual activity

Objectives A case of sudden sensorineural hearing loss following use of sildenafil was examined in detail over a period of three days from first report to recovery. Design Case study. The subject presented with sudden sensorineural hearing loss and diplacusis a day after onset. Testing involved detailed interview, standard audiometry, detailed inter-octave audiometry, and measurement of detailed psychophysical frequency tuning curves during a two day recovery period. Study Sample One male aged in his thirties with otherwise normal hearing. Results Although standard audiometry was within normal limits, detailed inter-octave audiometry and psychophysical frequency tuning curves were consistent with a punctate unilateral intra-cochlear lesion that resolved over a period of three days. Conclusions This is the first report of such a frequency-specific audiometric shift and diplacusis after sildenafil, and is not consistent with previous reports of direct ototoxic pharmacological effects. We propose that the lesion was most likely caused by a cochlear bleed, and may have been due to physical exertion rather than a direct pharmaceutical effect. The study highlights the important role of additional diagnostic testing that can be easily achieved in a clinical setting with minimal equipment

Colorimetric detection of neomycin sulfate in serum based on ultra-small gold nanoparticles with peroxidase-like activity

Neomycin sulfate (NEO) is a kind of aminoglycoside antibiotics. Because of its strong ototoxicity, nephrotoxicity and other side effects, its content in the body should be strictly monitored during use. In this paper, a rapid colorimetric detection method for NEO based on ultrasmall polyvinylpyrrolidone modified gold nanoparticles (PVP/Au NPs) with peroxidase-like activity was developed. Firstly, ultra small PVP/Au NPs with weak peroxidase-like activity were synthetized. When they were mixed with NEO, strong hydrogen bonds were formed between NEO and PVP, resulting in the aggregation of PVP/Au NPs, and the aggregated PVP/Au NPs showed stronger peroxidase-like activity. Therefore, rapid colorimetric detection of NEO was achieved by utilizing the enhanced peroxidase-like activity mechanism caused by the aggregation of ultra small PVP/Au NPs. The naked eye detection limit of this method is 50 nM. Within the range of 1 nM-300 nM, there was a good linear relationship between NEO concentration and the change in absorbance intensity of PVP/Au NPs-H2O2-TMB solution at 652 nm, with the regression curve of y = 0.0045x + 0.0525 (R2 = 0.998), and the detection limit is 1 nM. In addition, this method was successfully applied to the detection of NEO in mouse serum. The recoveries were 104.4 % −107.6 % compared with HPLC assay results, indicating that this method for NEO detection based on PVP/Au NPs has great potential in actual detection of NEO in serum.

Modulating the Unfolded Protein Response with ISRIB Mitigates Cisplatin Ototoxicity.

Cisplatin is a commonly used chemotherapy agent with a nearly universal side effect of sensorineural hearing loss. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate (STS), while beneficial when used in standard risk hepatoblastoma, is associated with reduced survival in disseminated pediatric malignancies, highlighting the need for more specific drugs without potential tumor protective effects. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo, and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin and UPR-modulating drugs, and UPR marker gene expression and cell death measured. Treatment with ISRIB, a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested in an in vivo mouse model of cisplatin ototoxicity and well as a head and neck squamous cell carcinoma (HNSCC) cell-based assay of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact the cytotoxic effects of cisplatin on HNSCC cell viability, unlike STS. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.

Awareness and Attitude About Ototoxic Drugs Among Medical Doctors in Arar City, Saudi Arabia.

The purpose of this study was to assess the awareness of ototoxicity among medical doctors in Arar City, Saudi Arabia. This is a cross-sectional study based on a pre-formed validated questionnaire (Appendix) that included three sections covering participants' demographic data (three questions), their attitudes (five questions), and knowledge (13 questions) regarding drug-induced ototoxicity. After obtaining their informed consent, 213 physicians from government and private sector health facilities in Arar were enrolled in the study. Interns and general practitioners represented 57.8% of the participants; consultants represented 17.8%. Only 71.8% of participants were interested in drug-induced ototoxicity, while 26.3% considered ototoxicity a rare complication. Approximately 90% of the participants were knowledgeable about the adverse effects of drugs on the vestibulocochlear system, and 26.7% reported having experienced cases of drug-induced ototoxicity in their practice. Participants showed an overall knowledge score about ototoxicity of 9.3±3.27 (out of 14). The knowledge score was significantly higher (p-value=0.0007) for participants with more years of clinical experience. The most widely known ototoxic drug for participants was frusemide (72.3%), followed by aminoglycoside (68.5%), while acetaminophen (44.1%) ototoxicity was the least known among participants. Awareness of drug-induced ototoxicity is satisfactory among physicians in the Northern Borders region. However, workshops about all types of drugs with ototoxic effects and the main lines for the management of drug-induced ototoxicity are recommended to increase awareness.

Feasible mechanisms and therapeutic potential of food probiotics to mitigate diabetes‐associated cancers: A comprehensive review and in silico validation

AbstractPeople with diabetes mellitus (DM) and hyperglycemia are linked with cancer risk. Diabetes and cancer have been corroborated by high morbidity and mortality rates. Studies revealed that elevated levels of insulin secretions trigger insulin‐like growth factor 1 (IGF‐1) production. Moreover, IGF‐1 is a key regulator involved in promoting cancer cell progression and is linked with DM. Cancer drug resistance and ototoxic effects can adversely affect the health and lifespan of an individual. However, naturally derived bioactive compounds are gaining attention for their nontoxic properties and specific behavior. Likewise, probiotics have also been regarded as safe and successful alternatives to treat DM‐linked cancers. The present review aims to highlight the therapeutic potential and feasible functions of probiotics to mitigate or inhibit DM‐associated cancers. Meanwhile, the intracellular signaling cascades involved in promoting DM‐linked cancer are enumerated for future prospective research. However, metabolomics interactions and protein–protein interactions are to be discussed for deeper insights into affirmative principles in diabetic‐linked cancers. Drug discovery and innovative preclinical evaluation need further adjuvant and immune‐enhancement therapies. Furthermore, the results of the in silico assessment could provide scientific excellence of IGF‐1 in diabetes and cancer. Overall, this review summarizes the mechanistic insights and therapeutic targets for diabetes‐associated cancer.

Fluoxetine, fluvoxamine, and hearing loss or tinnitus after cisplatin treatment: A retrospective cohort study.

Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.

Ototoxicity among cisplatin, carboplatin, and oxaliplatin in zebrafish model.

Platinum-based antineoplastic drugs, including cisplatin, carboplatin, and oxaliplatin, are widely used in the treatment of various cancers. Ototoxicity is a common adverse effect of platinum-based drugs. Ototoxicity leads to irreversible hearing impairment. We hypothesize that different platinum-based drugs exhibit varying ototoxic concentrations, time effects, and ototoxic mechanisms. We tested this hypothesis by using a zebrafish model (pvalb3b: TagGFP) to assess the viability of hair cells collected from zebrafish larvae. Cisplatin, carboplatin, and oxaliplatin were administered at dosages of 100, 200, or 400 μM, and the ototoxic effects of these drugs were assessed 1, 2, or 3 h after administration. Fm4-64 and a TUNEL assay were used to label the membranes of living hair cells and to detect cell apoptosis, respectively. We observed that >50% of hair cells were damaged at 1 h after cisplatin (100 μM) exposure, and this ototoxic effect increased at higher dosages and over time. Owing to the smaller ototoxic effects of carboplatin and oxaliplatin, we conducted higher-strength and longer-duration experiments with these drugs. Neither carboplatin nor oxaliplatin was obviously ototoxic, even at 1600 μM and after 6 h. Moreover, only cisplatin damaged the membranes of the hair cells. Cell apoptosis and significantly increased antioxidant gene expression were observed in only the cisplatin group. In conclusion, cisplatin significantly damages sensory hair cells and has notable dosage and time effects. Carboplatin and oxaliplatin are less ototoxic than cisplatin, likely due to having different ototoxic mechanisms than cisplatin.

Recent pathogenetic aspects of hearing loss in COVID: A literature review

The World Health Organisation predicts that by 2050, up to 10% of the world's population will need rehabilitation to address disability-related hearing loss. The purpose of this study was to identify the main mechanisms of hearing loss associated with Severe Acute Respiratory Syndrome Coronavirus 2 infection. The study included modern English-language scientific publications, mainly those with a high citation index, through the professional platforms MEDLINE/PubMed and Index Medicus. A total of 48 sources were selected. Research papers devoted to the development of conductive or sensorineural hearing loss, which occurred directly as a result of a viral disease, or is associated with the processes that accompany it (treatment, concomitant pathology, vaccination, etc.), were analysed. It was found that the development of viral-induced hearing loss in COVID has a multifactorial nature. The heterogeneity of audiological changes is primarily conditioned by direct viral damage to auditory analyser cells that express membrane receptors of the angiotensin converting enzyme of the second type. In addition, there is a reactivation of latent viral infection, extravasation of exudate into the middle ear cavity, blood clotting disorders, immune-mediated cell damage, local and generalised inflammatory reactions that affect both sound conduction and sound perception in one ear or both. Some cases of audiological disorders may also be of iatrogenic origin, since post-vaccination complications and ototoxic effects of medications used in the treatment of COVID-19 are not excluded, which should be considered by clinicians at all levels of healthcare to effectively manage a specific clinical scenario

Rutin Attenuates Gentamycin-induced Hair Cell Injury in the Zebrafish Lateral Line via Suppressing STAT1.

Aminoglycoside antibiotics, including gentamicin (GM), induce delayed ototoxic effects such as hearing loss after prolonged use, which results from the death of hair cells. However, the mechanisms underlying the ototoxicity of aminoglycosides warrant further investigation, and there are currently no effective drugs in the clinical setting. Herein, the therapeutic effect of the flavonoid compound rutin against the ototoxic effects of GM in zebrafish hair cells was investigated. Animals incubated with rutin (100-400 µmol/L) were protected against the pernicious effects of GM (200 µmol/L). We found that rutin improves hearing behavior in zebrafish, and rutin was effective in reducing the number of Tunel-positive cells in the neuromasts of the zebrafish lateral line and promoting cell proliferation after exposure to GM. Subsequently, rutin exerted a protective effect against GM-induced cell death in HEI-OC1 cells and could limit the production of cytosolic reactive oxygen species (ROS) and diminish the percentage of apoptotic cells. Additionally, the results of the proteomic analysis revealed that rutin could effectively inhibit the expression of necroptosis and apoptosis related genes. Meanwhile, molecular docking analysis revealed a high linking activity between the molecular docking of rutin and STAT1 proteins. The protection of zebrafish hair cells or HEI-OC1 cells from GM-induced ototoxicity by rutin was attenuated by the introduction of STAT1 activator. Finally, we demonstrated that rutin significantly improves the bacteriostatic effect of GM by in vitro experiments, emphasising its clinical application value. In summary, these results collectively unravel a novel therapeutic role for rutin as an otoprotective drug against the adverse effects of GM.

St. Jude Survivorship Portal: Sharing and Analyzing Large Clinical and Genomic Datasets from Pediatric Cancer Survivors.

Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. More than 1,600 phenotypic variables and 400 million genetic variants from more than 7,700 childhood cancer survivors can be explored on this free, open-access portal. Summary statistics of variables are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be customized and/or divided into groups for comparative analysis. Users can also seamlessly perform cumulative incidence and regression analyses on the stored survivorship data. Using the portal, we explored the ototoxic effects of platinum-based chemotherapy, uncovered a novel association between mental health, age, and limb amputation, and discovered a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry. Significance: The St. Jude Survivorship Portal is the first data portal designed to share and explore clinical and genetic data from childhood cancer survivors. The portal provides both open- and controlled-access features and will fulfill a wide range of data sharing needs of the survivorship research community and beyond. See co-corresponding author Xin Zhou discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932617204/7d99fa4958.

Abstract 6385: St. Jude Survivorship Portal: Sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors

Abstract Survivors of childhood cancer are at risk for developing various adverse health conditions as adults that are attributable to the cancer and treatments they were exposed to as children. Cancer survivorship research relies on large-scale, longitudinal studies that generate a wide range of demographic, clinical, and genetic data on cancer survivors. Nevertheless, the absence of cancer survivorship data portals has made it challenging to broadly share cancer survivorship data. We have created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing childhood cancer survivorship data. The portal hosts data from two large cohorts of pediatric cancer survivors: the St. Jude Lifetime Cohort Study (SJLIFE) and the Childhood Cancer Survivor Study (CCSS). Over 1,600 clinical variables and over 400 million genetic variants from over 7,700 childhood cancer survivors are stored on the portal. The data can be explored using an interactive data dictionary and a genome browser specialized for population genetics analysis. Summary statistics of variables and genetic variants are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be filtered or customized and may also be divided into groups for comparative analysis. Tools for performing cumulative incidence and regression analyses have been integrated into portal environment, allowing users to perform real-time statistical analyses on the stored survivorship data. Finally, users may also download individual-level clinical and genotype data from the portal using the controlled-access data download feature. Through various use-cases of survivorship research, we used the portal to explore the ototoxic effects of platinum-based chemotherapy, uncover a novel association between limb amputation, age, and long-term mental health, and identify a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry. The St. Jude Survivorship Portal provides a comprehensive, powerful, and easy-to-use interface for sharing and analyzing childhood cancer survivorship data that will serve as a valuable research tool for the broader survivorship research community. Citation Format: Gavriel Matt, Edgar Sioson, Jian Wang, Congyu Lu, Airen Zaldívar Peraza, Karishma Gangwani, Robin Paul, Colleen Reilly, Aleksandar Acić, Kyla Shelton, Qi Liu, Stephanie Sandor, Clay McLeod, Weiyu Qiu, Jaimin Patel, Fan Wang, Cindy Im, Zhaoming Wang, Carmen L. Wilson, Nickhill Bhakta, Kirsten Ness, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Jinghui Zhang, Yutaka Yasui, Xin Zhou. St. Jude Survivorship Portal: Sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6385.

Assessment of gentamicin dosing and monitoring in neonates: A single center experience.

Gentamicin is a commonly used medication in NICUs. It is known to have ototoxic & nephrotoxic side effects. To date there is no consensus about dosing regimen in different institutions. Our study aims to evaluate the Neofax® dosing regimen for gentamicin in neonatal early onset sepsis in relation to trough level before the second dose and its association with the incidence of gentamicin side effects, namely hearing impairment/loss and acute kidney injury. Retrospective chart review of newborns admitted to Tawam hospital NICU (June 2019-May 2020) who received gentamicin for early onset sepsis (≤72 hours old). Trough levels before the second dose at 24,36 and 48 hours were reviewed (≥1 mg/L is high). Excluded patients with renal risk factors. Side effects (hearing impairment, acute renal injury) were also assessed. Total of 265 infants were included, among whom 149 patients received gentamicin at 24 hours interval, 99 at 36 and 17 at 48 hours interval. Trough level was high in 76% (P = 0.022), 65% (P = 0.127), and 53% (P = 0.108) of patients who received gentamicin at 24, 36, and 48 hours, respectively. Hearing screening was normal in 99.2% of patients, while 2 patients failed the test (Both with normal trough levels). No patients in our study developed renal injury related to gentamicin use. Neofax® gentamicin dosing often results in high trough levels, especially in late preterm/term infants. This study found no correlation between high trough levels and hearing impairment upon discharge or acute kidney injury. Further studies with larger sample size are recommended.

Hearing Loss in Systemic Onset Juvenile Idiopathic Arthritis (Sojia) -A Single Case Study

Juvenile Rheumatoid Arthritis is a common type of arthritis in children under the age of sixteen. Females are more affected than males with ratio of 2:1. Systemic onset Juvenile Idiopathic Arthritis (SoJIA) is an immune driven inflammatory condition that develops in children. Although SoJIA can occur any time during childhood it usually starts before age five. Inflammation of internal organs and MAS (macrophage activation syndrome) is closely associated with SoJIA. Children with SoJIA have high levels of two powerful inflammatory protein (cytokines) called Interleukin -1 and Interleukin-6. The management of SoJIA follows up with NSAIDs, Corticosteroids, DMARDs and inflammatory cytokine blockade. The incudomalleolar and incudostapedial joint are synovial in nature and hence could be involved in inflammatory process. Immune complex mediated vasculitis and ototoxic side effects may cause a pathological inner ear. Thus individuals with SoJIA are at higher risk of hearing impairment.

Inhibition of the HMGB1/RAGE axis protects against cisplatin-induced ototoxicity via suppression of inflammation and oxidative stress.

As an anti-tumor drug widely used in the clinic, cisplatin is limited by its ototoxic side effects associated with various factors, including inflammatory responses. Receptor for Advanced Glycation Endproducts (RAGE) recognizes damage-associated molecular patterns (DAMPs) and promotes stress and inflammation. This study intended to determine the potential behavior of the HMGB1/RAGE axis after cisplatin injury and whether it has a protective effect after inhibiting this pathway. We used FPS-ZM1, a RAGE inhibitor, to modulate the axis of HMGB1/RAGE in neonatal mouse cochlear explants and C57BL/6 mice in vivo. Apoptosis was identified by Annexin V-FITC/PI assay, Cleaved Caspase-3, and TUNEL staining. Reactive oxygen species (ROS) level was assessed by MitoSOX Red and CellROX Green assay. The expression of proteins associated with the HMGB1/RAGE axis and apoptosis was observed by western blotting. The expression of inflammatory cytokines was evaluated by qPCR. The protective effect of HMGB1/RAGE knockdown was also assessed on cisplatin-induced ototoxicity. These results demonstrated that cisplatin could activate the HMGB1/RAGE pathway in cochlear hair cells and release inflammatory factors. Pretreatment with FPS-ZM1 alleviated cisplatin-induced ototoxicity in vivo and in vitro. Knocking down HMGB1 and RAGE achieved specific protective effects. Altogether, inhibiting HMGB1/RAGE axis can reverse the increase of ROS accumulation, the activation of apoptosis, and the production of inflammatory reactions after cisplatin injury. FPS-ZM1 could resist the ototoxicity of cisplatin by suppressing the HMGB1/RAGE signal pathway, and it may be considered the new otoprotective potential strategy for hearing loss.