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AbstractBackgroundAim/objectivesMaterial and MethodsResultsConclusionsHematopoietic stem cell transplantation (HSCT) is a critical treatment for various hematologic malignancies but can lead to complications, including ototoxicity.This study aims to explore the relationship between patient-specific factors and ototoxicity in adult HSCT patients.We conducted a retrospective analysis of 129 adult patients who underwent HSCT between 2003 and 2020. Age, gender, transplant indications, conditioning regimens, and pre- and post-transplant audiometry thresholds data were collected from patient files. A hearing loss of 10 decibels or more at two consecutive frequencies or a hearing loss of 20 decibels or more at a single frequency was considered as significant hearing loss (SHL). Statistical analyses were performed to describe factors associated with SHL.SHL occurred in 16.3% of patients. Older age was significantly associated with an increased risk of SHL (p = .035). Poorer pretransplant hearing thresholds at 4000 Hz and 6000 Hz were also significant predictors of SHL (p = .039 and p = .014, respectively). There was no significant relationship between the donor type of HSCT (autologous vs. allogeneic) and ototoxicity (p = .45), and between conditioning regimens and ototoxicity (p = .860).Age and pre-existing hearing levels are significant predictors of ototoxicity post-HSCT. Careful management and monitoring are essential to prevent and address hearing loss in HSCT patients to improve hearing-related quality of life. [ABSTRACT FROM AUTHOR]

Aim: To describe treatment-induced toxicities (TITs) and associated factors in Zimbabwean cancer patients receiving cisplatin. Methods: In total, 252 Zimbabwean women with cervical cancer, receiving cisplatin were followed up over 12 months for TITs and disease status. Results: Peripheral neuropathy (70%) and ototoxicity (53%) were most prevalent. Advanced disease (OR = 1.3; 95% CI = 1.1–1.5; p = 0.02), pain comedications (OR = 1.3; 95% CI = 1.1–1.5; p = 0.03), alcohol (OR = 2.8; 95% CI = 1.1–7.5; p = 0.04) and comorbidities (OR = 1.2; 95% CI = 1.1–1.4; p = 0.04) increased peripheral neuropathy and ototoxicity risk. Older age increased risk of disease progression (OR = 1.9; 95% CI = 1.4–3.0; p = 0.033). Conclusion: High peripheral neuropathy and ototoxicity prevalence were observed, which are not routinely monitored in Zimbabwe. There is a need for capacity building to incorporate comprehensive TIT testing and optimize cancer care in Zimbabwe. Plain Language Summary Cancer treatment has side effects, also known as treatment-induced toxicities (TITs), that can lead to death if not management properly. African populations are more likely to develop TITs, however, not many studies research on TITs in Africans and why they are more prone to TITs. This study followed up 252 Zimbabwean women with cervical cancer, over 12 months for TITs and found that loss of sensation and ear complications most commonly occurred after treatment. Advanced disease, prescribed pain medication, alcohol consumption history and underlying diseases such as diabetes increased likelihood of TITs, while older age increased risk of unresponsive cancer. This study highlights a need to incorporate comprehensive monitoring for TITs for at-risk individuals toward improving cancer care. Article highlights Peripheral neuropathy and ototoxicity are common in Zimbabwean cancer patients, even though they are not routinely monitored in oncology facilities. Clinical factors such as comorbid conditions, pain co-medications and high cisplatin dose increase the risk of developing treatment-induced toxicities (TITs). High BMI was a predictor of peripheral neuropathy development. Lifestyle factors such as history of alcohol consumption can increase the risk of treatment-induced toxicities. In this study, HIV was not a risk factor for any of the TITs and treatment outcomes such as relapse, disease progression and mortality. Older patients are more prone to poor prognosis compared with younger patients highlighting a need for cancer screening even beyond the prescribed age of 40 years. Comprehensive TIT monitoring should be implemented in Zimbabwe primary care for cancer patients, to include peripheral neuropathy and ototoxicity, toward improving patient management. More studies to describe TITs in low-resource settings such as Zimbabwe are required in order to personalize medicine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Cisplatin‐induced sensorineural hearing loss is a significant clinical challenge. Although the potential effects of brain‐derived neurotrophic factor (BDNF) have previously been investigated in some ototoxicity models, its efficacy in cisplatin‐induced hearing loss remains uncertain. This study aimed to investigate the therapeutic potential of recombinant human BDNF (rhBDNF) in protecting cells against cisplatin‐induced ototoxicity.Using an in vivo model of cisplatin‐induced hearing loss, we investigated the beneficial effects of transtympanic administration of rhBDNF in a thermogel solution on hearing function and cochlear injury, using electrophysiological, morphological, immunofluorescence and molecular analyses.Our data showed that local rhBDNF treatment counteracted hearing loss in rats receiving cisplatin by preserving synaptic connections in the cochlear epithelium and protecting hair cells (HCs) and spiral ganglion neurons (SGNs) against cisplatin‐induced cell death. Specifically, rhBDNF maintains the balance of its receptor levels (pTrkB and p75), boosting TrkB‐CREB pro‐survival signalling and reducing caspase 3‐dependent apoptosis in the cochlea. Additionally, it activates antioxidant mechanisms while inhibiting inflammation and promoting vascular repair.Collectively, we demonstrated that early transtympanic treatment with rhBDNF plays a multifaceted protective role against cisplatin‐induced ototoxicity, thus holding promise as a novel potential approach to preserve hearing in adult and paediatric patients undergoing cisplatin‐based chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: The effectiveness of audiological monitoring for detecting early hearing changes in patients receiving ototoxic medication could be limited by the lack of adequate audiological ototoxicity monitoring (OtoM) guidelines. This study aimed to evaluate existing OtoM guidelines using the AGREE II tool for guideline evaluation. Design: Guideline Review. Study Sample: Three audiological OtoM guidelines. Results: An online search identified three audiological OtoM guidelines published by the American Speech-Language and Hearing Association (ASHA), the American Academy of Audiology (AAA) and the Health Professionals Council of South Africa (HPCSA). Evaluation using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool found the HPCSA audiological OtoM guideline scored higher than the ASHA and AAA guidelines in five of the six tool domains. All guidelines received average domain ratings of less than 50% with each reviewer recommending all three guidelines for use following modification. Conclusion: The findings of this study could partly explain the poor uptake of audiological OtoM practices internationally, further investigation is needed to identify the specific factors limiting the implementation of audiological OtoM in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: The threat of hearing loss has become a universal reality. Gentamycin (GM) can lead to ototoxicity and may result in permanent hearing loss. This study aimed to elucidate whether the hypolipidemic drug Ezetimibe (EZE) has a possible underlying mechanism for protecting rats from GM-induced ototoxicity. Methods and results: 30 male Wister albino rats were separated into three groups, ten in each group: control, GM, and GM + EZE. At the end of the experiment, rats underwent hearing threshold evaluation via auditory brainstem response (ABR), carotid artery blood flow velocity (CBV), and resistance (CVR) measurement, in addition to a biochemical assessment of serum malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), hemeOxygenase-1 (HO-1), and tumor necrosis factor-α (TNF-α). Also, real-time PCR was employed to quantify the levels of brain-derived neurotrophic factor (BDNF). Cochlea was also studied via histological and immunohistochemical methods. GM revealed a significant increase in CVR, MDA, NO, and TNF-α and a significant decrease in ABR, CBV, CAT, HO-1, and cochlear BDNF expression. EZE supplementation revealed a significant rise in ARB in addition to CBV and a decline in CVR and protected cochlear tissues via antioxidant, anti-inflammatory, and antiapoptotic mechanisms via downregulating Caspase-3 immunoreaction, upregulating proliferating cellular nuclear antigen (PCNA) immunoreaction, and upregulating of the cochlear BDNF expression. Correlations were significantly negative between BDNF and MDA, NO, TNF-α, COX 2, and caspase-3 immunoreaction and significantly positive with CAT, HO-1, and PCNA immunoreaction. Discussion: EZE can safeguard inner ear tissues from GM via antioxidant, anti-inflammatory, and antiapoptotic mechanisms, as well as upregulation of BDNF mechanisms. [ABSTRACT FROM AUTHOR]

[Display omitted] • CORM-2 attenuates cisplatin-induced hearing loss in young adult mice. • CORM-2 co-treatment decreases platinum accumulation in the inner ear. • CORM-2 protects against cisplatin-induced toxic cellular responses including necroptosis, plasma membrane disruption, and apoptotic cell death. • CORM-2 co-treatment reverses the persistent inflammatory environment created by cisplatin. • CORM-2 co-treatment reduces cochlear capillary leakage (hyperpermeability) and maintains the integrity of blood-labyrinth barrier. Cisplatin is a life-saving anticancer compound used to treat multiple solid malignant tumors, while it causes permanent hearing loss. There is no known cure, and the FDA has not approved any preventative treatment for cisplatin-based ototoxicity. This study investigated whether the carbon monoxide (CO)-releasing tricarbonyldichlororuthenium (II) dimer, CORM-2, reverses cisplatin-induced hearing impairment and reduces cisplatin accumulation in the mouse inner ear. Male 6-week-old BALB/c mice were randomly assigned to one of the following groups: control (saline-treated, i.p.), CORM-2 only (30 mg/kg, i.p., four doses), cisplatin only (20 mg/kg, i.p., one dose), and CORM-2 + cisplatin, to determine whether cisplatin-based hearing impairment was alleviated by CORM-2 treatment. Our results revealed CORM-2 significantly attenuated cisplatin-induced hearing loss in young adult mice. CORM-2 co-treatment significantly decreased platinum accumulation in the inner ear and activated the plasma membrane repair system of the stria vascularis. Moreover, CORM-2 co-treatment significantly decreased cisplatin-induced inflammation, apoptosis, and cochlear necroptosis. Because the stria vascularis is the likely cochlear entry point of cisplatin, we next focused on the microvasculature. Cisplatin induced increased extravasation of a chromatic tracer (fluorescein isothiocyanate [FITC]-dextran, MW 75 kDa) around the cochlear microvessels at 4 days post-treatment; this extravasation was completely inhibited by CORM-2 co-therapy. CORM-2 co-treatment effectively maintained the integrity of stria vascularis components including endothelial cells, pericytes, and perivascular-resident macrophage-type melanocytes. CORM-2 co-therapy substantially protects against cisplatin-induced ototoxicity by reducing platinum accumulation and toxic cellular stress responses. These data indicate that CORM-2 co-treatment may be translated into clinical strategy to reduce cisplatin-induced hearing loss. [ABSTRACT FROM AUTHOR]

Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics (gentamicin, amikacin, neomycin) and platinum anti-tumor drugs (cisplatin, carboplatin). The inner ear and kidney share similarities in drug deposition and toxicity, but the underlying pathophysiological mechanisms remain unclear. Investigating the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy. A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two organs. The primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets (LDs) and more interactions between mitochondria and LDs, leading to a sequence of disturbances in lipid metabolism, such as increased lipid ROS and the blocked transfer of fatty acids from LDs to mitochondria. PGC-1 α deficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs, as indicated by the exacerbated disturbance of dynamic LD turnover, increased level of oxidized lipids and decreased use of fatty acids. This investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria–LD interactions in drug-induced ototoxicity and nephrotoxicity, potentially providing novel avenues for intervention strategies. Selective accumulation of neomycin in hair cells and renal tubular epithelial cells induces ototoxicity and nephrotoxicity, characterized by lipid deposition and mitochondrial dysfunction. PGC-1 α −/− exacerbates the imbalance of mitochondria-lipid droplet homeostasis. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: A number of drugs are toxic to the cochlear sensory cells known as hair cells (HCs), resulting in hearing loss. Treatment with survival-promoting growth factors, antioxidants, and inhibitors of cell death pathways or proteinases have been shown to reduce HC damage in in vivo and/or in vitro animal models. Conversely, translation to humans has often been disappointing. This may be due to the complexity of intracellular damage processes. We hypothesized that combining treatments targeting different cellular processes would be more effective. Methods: Using an in vitro model of gentamicin ototoxicity for murine cochlear hair cells, we screened all 56 possible combinations of inhibitors targeting five different cell damage mechanisms, plus the activator of one cell survival pathway, each of which have been shown to be singly effective in preventing HC loss in experimental studies. A high dose of gentamicin (200 µM) was used over three days in culture. All compounds were added at a dosage below that required for significant protection in the assay, and only this single dose was then employed. This was done so that we could more easily detect interactive, as opposed to additive, effects. Results: Increasing protection of hair cells was observed as combinations of compounds were increased from two to four factors, although not all combinations were equally protective. The optimal combination of four compounds consisted of an anti-oxidant, an apoptosis inhibitor, an autophagy inhibitor and a protective growth factor. Increasing the number of factors to five or six resulted in decreased protection. Conclusion: The results support the hypothesis that targeting multiple cellular damage or survival pathways provides more an effective hair cell protection approach. The results help to identify critical interactions among the cellular processes that operate in gentamicin ototoxicity. They also suggest that inhibiting too many biological processes impairs functions critical to HC survival, resulting in decreased protection. [ABSTRACT FROM AUTHOR]

Simple Summary: Sensorineural hearing loss is a common late complication among nasopharyngeal cancer survivors, primarily due to the close proximity of the auditory apparatus to the treatment volume and the use of cisplatin-based chemotherapy. The incidence of hearing loss in the era of intensity-modulated radiation therapy varies widely, influenced by factors such as patient demographics, auditory assessment methods, and the duration of follow-up. While guidelines have provided recommendations on radiation dose constraints to the cochlea to mitigate hearing loss, significant risks remain. To improve hearing outcomes, strategies such as radiotherapy de-escalation, personalized treatment planning, and the consideration of alternative systemic agents in localized nasopharyngeal cancer are being investigated. This review discusses the context and relevant evidence regarding potential strategies to improve hearing outcomes in this patient population. Intensity-modulated radiation therapy (IMRT) improves disease control and reduces treatment-related toxicity in patients with localized nasopharyngeal carcinoma (NPC). However, due to the proximity of the auditory apparatus to the treatment volume and the frequent incorporation of cisplatin-based chemotherapy, treatment-related sensorineural hearing loss (SNHL) remains a common debilitating complication among NPC survivors. The reported crude incidence of SNHL following IMRT for NPC varies widely at 1–46% due to differences in auditory assessment methods and thresholds, follow-up durations, chemotherapy usage, and patient compositions. International guidelines and radiation dosimetric studies have recommended constraining the cochlear mean dose to less than 44–50 Gy, but the risk of SNHL remains high despite adherence to these constraints. Potential strategies to improve hearing outcomes in NPC survivors include cautious de-escalation of radiotherapy dose and volume, individualization of cochlear constraints, optimization of radiotherapy planning techniques, and the use of substitutes or alternative schedules for cisplatin-based chemotherapy. The addition of immune checkpoint inhibitors to chemoradiotherapy did not impact ototoxicity. Prospective studies that employ both objective and patient-reported auditory outcomes are warranted to test the long-term benefits of various approaches. This article aims to provide a comprehensive review of the incidence and radiation dose–toxicity relationship of SNHL in NPC survivors and to summarize potential strategies to optimize hearing outcomes in relation to nuances in radiotherapy planning and the selection of systemic therapy. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to identify and clinically characterize patients treated in an Otoneurology Unit who experienced vestibular ototoxicity as a result of using aminoglycoside ear drops during outbreaks of superinfection in chronic otitis media. Material and Methods: An observational retrospective study was conducted, including patients with perforated eardrums who developed vestibular ototoxicity within the past 10 years following the application of topical ear aminoglycosides in a tertiary referral center. The study encompassed the assessment of the clinical presentation, treatment, quality of life, and evolution after treatment of the identified individuals. Results: During the study period, 6 patients, aged between 33 and 71 years, developed vestibular ototoxicity following the use of topical aminoglycoside drops due to infection flares in chronic otitis media. All cases involved the use of gentamicin. Two cases were unilateral, and 4 were unilateral. The onset of symptoms occurred within one to four weeks of using the drops, resulting in all patients experiencing instability without vertigo attacks. After discontinuing the drops and undergoing vestibular rehabilitation, 4 patients experienced sequelae, with 2 patients (both with bilateral vestibular hypofunction) suffering significant impairment in their quality of life. Conclusions: Vestibular ototoxicity due to the topical application of aminoglycosides during acute exacerbations of chronic otitis media is a rare occurrence. However, given its potential for severe consequences and the fact that we are still encountering patients with this condition, healthcare professionals should explore alternative antibacterial agents that offer similar efficacy. [ABSTRACT FROM AUTHOR]

We studied the function of the auditory system in Wistar rats after repeated intravenous administration of nicotinamide riboside (NR). The functional activity of the receptor and retrocochlear parts of the auditory system were assessed by recording short-latency auditory evoked potentials (SLAEPs) and distortion-product otoacoustic emissions (DPOAEs) at baseline, immediately after NR administration, and 1 and 2 months later. Repeated intravenous NR administration (cumulative dose of 2700 mg/kg) to Wistar rats has a detrimental impact on the structures within the cochlear section of the auditory system. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the current scoping review is to identify the studies reporting ototoxicity monitoring in individuals with head and neck cancer (HNC) undergoing radiation therapy and/or chemoradiation therapy across the world. The specific objectives were to identify and report the test protocol used, identify the most common timeline of follow-up, and identify barriers and facilitators influencing the implementation of the monitoring program. Method: A comprehensive search was conducted across six electronic databases, including PubMed, Embase, Web of Science, Scopus, Google Scholar, and ProQuest. The scoping review method adhered to relevant guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) and frameworks. The database search was carried out by two independent researchers, and studies were selected based on specific inclusion and exclusion criteria. Results: This scoping review identified 13 studies that fulfilled the inclusion criteria of this study. Only one study reported findings from the perspective of ototoxicity monitoring. Another study explicitly mentioned that ototoxicity monitoring was a standard of care in their hospital. Only one study reported using the relevant guidelines for monitoring ototoxicity. Specialized tests such as high-frequency audiometry, distortion product otoacoustic emissions, and vestibular tests were rarely used. Ototoxicity monitoring was influenced by awareness-related factors, technical factors, treatment-related factors, and organizational factors. Conclusions: Research on ototoxicity monitoring programs is in its early stages, highlighting the need for standardized practices and multidisciplinary collaboration to enhance health care services for HNC patients. A standardized approach, improved awareness, and the incorporation of patient perspectives are crucial to enhancing ototoxicity monitoring in HNC patients. [ABSTRACT FROM AUTHOR]

Cisplatin is a chemotherapeutic agent widely used to treat solid tumors. However, it can also be highly ototoxic, resulting in high-frequency hearing loss. Cisplatin causes degeneration of hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear, which are essential components of the hearing process and cannot be regenerated in mammals. As the affected cells primarily die by apoptosis, we tested several anti-apoptotic small molecules to protect these cells from drug-induced toxicity. We found that the general caspase inhibitor Emricasan could significantly counteract the toxic effects of cisplatin in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, phoenix auditory cells, and primary SGNs. Importantly, the anti-cytotoxic effect in neuronal cells was even more pronounced than the effect of sodium thiosulfate (STS), which is currently the only approved prevention option for cisplatin-induced ototoxicity. Finally, we tested the protective effect of Emricasan treatment in the context of another ototoxic drug, i.e., the aminoglycoside antibiotic neomycin, and again found a significant increase in cell viability when the cultures were co-treated with Emricasan. These results suggest a promising strategy to prevent ototoxicity in patients by temporarily blocking the apoptotic pathway when applying cisplatin or aminoglycoside antibiotics. Key messages: Anti-apoptotic small molecules can reduce cisplatin-induced toxicity. Emricasan can effectively exert its anti-apoptotic effect on cochlear cells. Strong protection from cisplatin- and neomycin-induced cytotoxicity with Emricasan. Sodium thiosulfate and Emricasan provide similar protective effects to cisplatin-treated cells. Emricasan is more potent than sodium thiosulfate in reducing neomycin-induced cytotoxicity. [ABSTRACT FROM AUTHOR]

Aminoglycosides (AGs) are a class of antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs. This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs, therefore referred to as genkamicins (GKs). The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases. A series of novel hybrid aminoglycoside antibiotics were created by glycosyltransferase swapping, one of which retained antimicrobial activity but low ototoxicity, making it a candidate for further development as an antibiotic with improved safety. [Display omitted] [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

Stress granules (SGs) are highly dynamic micromolecular membraneless condensates that generate in cells subjected to stress. Formed from pools of untranslating messenger ribonucleoproteins (RNP), SGs dynamics constitute vital processes essential for cell survival. Here, we investigate whether established cytotoxic agents, such as the platinum-based chemotherapeutic agent cisplatin and the aminoglycoside antibiotic gentamicin, elicit SG formation in the House Ear Institute-Organ of Corti-1 (HEI-OC1) auditory cell line, H4 human neuroglioma cells and HEK-293T human embryonic kidney cells. Cells were treated with cisplatin or gentamicin for specific durations at designated concentrations. SG formation was assessed using immunocytochemistry and live cell imaging. Levels of essential proteins involved in SG assembly were evaluated using immunoblotting. We observed cisplatin-associated SG assembly in HEI-OC1 and H4 cells via confocal microscopy through antibody colabeling of G3BP1 with PABP or Caprin1. While maintaining an unchanged pattern of expression of main constituent SG proteins, cisplatin-related SGs in H4 cells persisted for at least 12 h after drug removal. Cells subjected to gentamicin exposure did not exhibit SGs. Our findings offer insights into subcellular mechanisms related to cisplatin-associated cytotoxicity, highlighting the need for future studies to further investigate this stress-response mechanism.

Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics (gentamicin, amikacin, neomycin) and platinum anti-tumor drugs (cisplatin, carboplatin). The inner ear and kidney share similarities in drug deposition and toxicity, but the underlying pathophysiological mechanisms remain unclear. Investigating the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy. A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two organs. The primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets (LDs) and more interactions between mitochondria and LDs, leading to a sequence of disturbances in lipid metabolism, such as increased lipid ROS and the blocked transfer of fatty acids from LDs to mitochondria. PGC-1α deficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs, as indicated by the exacerbated disturbance of dynamic LD turnover, increased level of oxidized lipids and decreased use of fatty acids. This investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria–LD interactions in drug-induced ototoxicity and nephrotoxicity, potentially providing novel avenues for intervention strategies.

Abstract 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 malignancy, 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 marker gene expression and cell death measured. Treatment with ISRIB (Integrated Stress Response InhIBitor), a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested for its ability to reduce apoptosis in HEK cells, hair-cell death in cochlear cultures, and hearing loss using an in vivo mouse model of cisplatin ototoxicity. Finally, to evaluate whether ISRIB might interfere with cisplatin chemoeffectiveness, we tested it in head and neck squamous cell carcinoma (HNSCC) cell-based assays 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 cisplatin’s cytotoxic effects 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.

Aminoglycosides (AGs) are a class of antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs. This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs, therefore referred to as genkamicins (GKs). The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.

Abstract Background Ototoxicity is a major side effect of many broadly used aminoglycoside antibiotics (AGs) and no FDA-approved otoprotective drug is available currently. The zebrafish has recently become a valuable model to investigate AG-induced hair cell toxicity and an expanding list of otoprotective compounds that block the uptake of AGs have been identified from zebrafish-based screening; however, it remains to be established whether inhibiting intracellular cell death pathway(s) constitutes an effective strategy to protect against AG-induced ototoxicity. Results We used the zebrafish model as well as in vitro cell-based assays to investigate AG-induced cell death and found that ferroptosis is the dominant type of cell death induced by neomycin. Neomycin stimulates lipid reactive oxygen species (ROS) accumulation through mitochondrial pathway and blocking mitochondrial ferroptosis pathway effectively protects neomycin-induced cell death. We screened an alkaloid natural compound library and identified seven small compounds that protect neomycin-induced ototoxicity by targeting ferroptosis pathway: six of them are radical-trapping agents (RTAs) while the other one (ellipticine) regulates intracellular iron homeostasis, which is essential for the generation of lipid ROS to stimulate ferroptosis. Conclusions Our study demonstrates that blocking intracellular ferroptosis pathway is an alternative strategy to ameliorate neomycin-induced ototoxicity and provides multiple hit compounds for further otoprotective drug development.

Background: Methyltransferase-like 3 (METTL3), a component of the N6-methyladenosine (m6A) methyltransferase family, exhibits significant expression in HEI-OC1 cells and cochlear explants. Aminoglycoside antibiotics, known for their ototoxic potential, frequently induce irreversible auditory damage in hair cells, predominantly through oxidative stress mechanisms. However, the specific role of METTL3 in kanamycin-induced hair cell loss remains unclear. Objective: This study aims to elucidate the mechanisms by which METTL3 contributes to kanamycin-induced ototoxicity. Methods and Results: In vivo experiments demonstrated a notable reduction in METTL3 expression within cochlear explants following kanamycin administration, concomitant with the formation of stress granules (SGs). Similarly, a 24-hour kanamycin treatment led to decreased METTL3 expression and induced SG formation both in HEI-OC1 cells and neonatal cochlear explants, corroborating the in vivo observations. Lentivirus-mediated transfection was employed to overexpress and knockdown METTL3 in HEI-OC1 cells. Knockdown of METTL3 resulted in increased reactive oxygen species (ROS) levels and apoptosis induced by kanamycin, while concurrently reducing SG formation. Conversely, overexpression of METTL3 attenuated ROS generation, decreased apoptosis rates, and promoted SG formation induced by kanamycin. Therefore, METTL3-mediated SG formation presents a promising target for mitigating kanamycin-induced ROS generation and the rate of apoptosis. Conclusion: This finding indicates that METTL3-mediated SG formation holds potential in mitigating kanamycin-induced impairments in cochlear hair cells by reducing ROS formation and apoptosis rates. [ABSTRACT FROM AUTHOR]

Sensorineural hearing loss (SNHL), characterized by damage to the inner ear or auditory nerve, is a prevalent auditory disorder. This study explores the potential of Castanopsis echinocarpa (CAE) as a therapeutic agent for SNHL. In vivo experiments were conducted using zebrafish and mouse models. Zebrafish with neomycin-induced ototoxicity were treated with CAE, resulting in otic hair cell protection with an EC50 of 0.49 µg/mL and a therapeutic index of 1020. CAE treatment improved auditory function and protected cochlear sensory cells in a mouse model after noise-induced hearing loss (NIHL). RNA sequencing of NIHL mouse cochleae revealed that CAE up-regulates genes involved in neurotransmitter synthesis, secretion, transport, and neuronal survival. Real-time qPCR validation showed that NIHL decreased the mRNA expression of genes related to neuronal function, such as Gabra1, Gad1, Slc32a1, CaMK2b, CaMKIV, and Slc17a7, while the CAE treatment significantly elevated these levels. In conclusion, our findings provide strong evidence that CAE protects against hearing loss by promoting sensory cell protection and enhancing the expression of genes critical for neuronal function and survival. [ABSTRACT FROM AUTHOR]

This study evaluated the diagnostic performances of a tablet-based hearing screening test by assisted-test and self-test modes. Measurements were performed with the SoTone tests in normal hearing and hearing-impaired adult participants using an Android tablet and calibrated Bluetooth headphones. The duration of assisted- and self-test modes were compared. Receiver operating characteristic (ROC) curves were plotted after calculations of sensitivity and specificity at 20, 30, and 35 dB HL cut-off values. 217 participants performed the tests. The effect of test mode (assisted versus self) was compared in a sample of 103 participants. Self-test duration (89 s) was significantly longer than the assisted-test duration (75 s) (p = 0.003, Wilcoxon test). For the 20, 30, and 35 dB HL cut-off values, sensitivity was between 92% and 96%, and specificity was between 79 and 90%. Concordance of results between assisted-test and self-test modes was excellent (Cohen's kappa = 0.81, p < 0.001). The SoTone hearing screening test is accurate for identifying the presence of a suspected hearing loss at 20 dB HL or more in adults. It can be used either in assisted-test or self-test modes. [ABSTRACT FROM AUTHOR]

Hearing loss is a health crisis that affects more than 60 million Americans. Currently, sodium thiosulfate is the only drug approved by the Food and Drug Administration (FDA) to counter hearing loss. Sirtuins were proposed as therapeutic targets in the search for new compounds or drugs to prevent or cure age-, noise-, or drug-induced hearing loss. Sirtuins are proteins involved in metabolic regulation with the potential to ameliorate sensorineural hearing loss. The mammalian sirtuin family includes seven members, SIRT1-7. This paper is a literature review on the sirtuins and their protective roles in sensorineural hearing loss. Literature search on the NCBI PubMed database and NUsearch included the keywords 'sirtuin' and 'hearing'. Studies on sirtuins without relevance to hearing and studies on hearing without relevance to sirtuins were excluded. Only primary research articles with data on sirtuin expression and physiologic auditory tests were considered. The literature review identified 183 records on sirtuins and hearing. After removing duplicates, eighty-one records remained. After screening for eligibility criteria, there were forty-eight primary research articles with statistically significant data relevant to sirtuins and hearing. Overall, SIRT1 (n = 29) was the most studied sirtuin paralog. Over the last two decades, research on sirtuins and hearing has largely focused on age-, noise-, and drug-induced hearing loss. Past and current studies highlight the role of sirtuins as a mediator of redox homeostasis. However, more studies need to be conducted on the involvement of SIRT2 and SIRT4-7 in hearing protection. [ABSTRACT FROM AUTHOR]

Although it is widely used, there is still no valid treatment for ototoxicity caused by the antineoplastic drug cisplatin. In this study, we aimed to investigate the efficacy of intratympanic resveratrol and intratympanic dexamethasone treatment in cisplatin-induced ototoxicity. We also compared intratympanic atosiban (oxytocin antagonist) and oxytocin in cisplatin ototoxicity. In this study, 30 rats (60 ears) were used by separating into 5 groups. Cisplatin, oxytocin, dexamethasone, atosiban and 0.9% NaCl were administered intraperitoneally to all groups separately. Auditory Brainstem Response and Distortion Product Otoacoustic Emission tests were performed on all groups before and 72 h after the procedure. Pre-treatment values were higher than post-treatment values in all groups (p < 0.001). There was no significant prolongation of the post-treatment Auditory Brainstem Response I-IV interval in the oxytocin and dexamethasone groups (p > 0.05). There was no significant decrease in the frequencies of 2832 and 4004 after treatment in the oxytocin and dexamethasone group compared to pre-treatment in Distortion Product Otoacoustic Emission. As a result, it has been shown that intratympanic oxytocin may be an option that can be used in the treatment, although it is not as effective as dexamethasone in preventing cisplatin ototoxicity. [ABSTRACT FROM AUTHOR]

Background: The ototoxicity of both chemotherapy and radiotherapy has been studied. Little is known regarding their impact on the vestibular system, particularly, the laboratory vestibular testing that evaluates the effects of both chemotherapy and radiotherapy on the peripheral and central vestibular system. Consequently, the current research was designed to study Videonystagmography (VNG) and video head impulse test (vHIT)in patients with head and neck cancer receiving chemotherapy and radiotherapy for early diagnosis of vestibularsystem abnormalities. Methods: This study included two groups with head and neck cancer: group I included 19 patients receiving chemotherapy and group II included 19 patients receiving radiotherapy. Basic audiological evaluation, VNG, and vHIT were conducted on all patients before treatment and 3 months following treatment. Results: Regarding pure tone audiometry, there was a statistically significant increase in hearing threshold at high frequencies in patients receiving chemotherapy and radiotherapy before and after treatment. As regards the VNG test, there was a statistically significant impairment in saccade, smooth pursuit, optokinetic, and caloric tests in patients before and after receiving chemotherapy. However, in patients receiving radiotherapy, there was no statistically significant difference in the VNG test battery except for increased value of caloric weakness. vHIT abnormalities were reported in patients of both groups. Conclusions: This study demonstrated the ototoxic and vestibulotoxic effects of both chemotherapy and radiotherapy in patients with head and neck cancer. [ABSTRACT FROM AUTHOR]

Aim: To explore the views of neonatal intensive care nursing staff on the deliverability of a novel genetic point‐of‐care test detecting a genetic variant associated with antibiotic‐induced ototoxicity. Design: An interpretive, descriptive, qualitative interview study. Methods: Data were collected using semi‐structured interviews undertaken between January and November 2020. Participants were neonatal intensive care nursing staff taking part in the Pharmacogenetics to Avoid Loss of Hearing trial. Results: Thematic analysis resulted in four themes: perceived clinical utility; the golden hour; point‐of‐care device; training and support. Recommendations were made to streamline the protocol and ongoing training and support were considered key to incorporating the test into routine care. Conclusion: Exploring the views of nurses involved in the delivery of the point‐of‐care test was essential in its implementation. By the study endpoint, all participants could see the value of routine clinical introduction of the point‐of care test. Implications for the Profession and/or Patient Care: Nurses are in a key position to support the delivery of point‐of‐care genetic testing into mainstream settings. This study has implications for the successful integration of other genetic point‐of‐care tests in acute healthcare settings. Impact: The study will help to tailor the training and support required for routine deployment of the genetic point‐of‐care test. The study has relevance for nurses involved in the development and delivery of genetic point‐of‐care tests in other acute hospital settings. Reporting Method: This qualitative study adheres to the Standards for Reporting Qualitative Research EQUATOR guidelines and utilizes COREQ and SRQR checklists. Patient or Public Contribution: All staff working on the participating neonatal intensive care units were trained to use the genetic point‐of‐care test. All inpatients on the participating units were eligible to have testing via the point‐of‐care test. The Pharmacogenetics to Avoid Loss of Hearing Patient and Public Involvement and Engagement group provided valuable feedback. Trial and Protocol Registration: Registered within the University of Manchester. Ethics approval reference numbers: IRAS: 253102 REC reference: 19/NW/0400. Also registered with the ISRCTN ref: ISRCTN13704894. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Cisplatin-based chemoradiation is a standard treatment for many patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), an etiologically distinct subset of head and neck cancer. Although associated with good long-term survival, clinical risk factors for ototoxicity have been understudied in this population. This study aimed to evaluate clinical predictors associated with ototoxicity in HPV-positive OPSCC patients treated with cisplatin chemoradiation. Methods: This retrospective case-control study included 201 adult patients (>18 years) with histologically confirmed HPV-positive OPSCC who received cisplatin chemoradiation as their primary treatment from 2001 and 2019 at a single tertiary cancer center. Ototoxicity was determined using baseline and follow-up audiometry and the Common Terminology Criteria for Adverse Events v5.0 grading criteria (Grade ≥2). Multivariable logistic regression [adjusted odds ratio (aOR)] identified significant predictors that increased the odds of ototoxicity. Results: A total of 201 patients [165 males; median (IQR) age, 57 (11) years] were included in the study. The incidence of ototoxicity in the worst ear was 56.2%, with the greatest hearing loss occurring at high frequencies (4-8 kHz), resulting in a loss of 12.5 dB at 4 to 6 kHz and 20 dB at 6 to 8 kHz. High-dose cisplatin administration compared to weekly administration [aOR 4.93 (95% CI: 1.84-14.99), P =.003], a higher mean cochlear radiation dose [aOR 1.58 (95% CI: 1.12-2.30), P =.01], smoking history [aOR 2.89 (95% CI: 1.51-5.63), P =.001], and a 10 year increase in age [aOR 2.07 (95% CI: 1.25-3.52), P =.006] were each independently associated with increased odds of ototoxicity. Conclusions: Clinical predictors of ototoxicity in HPV-positive OPSCC patients treated with cisplatin-based chemoradiation include the use of a high-dose cisplatin regimen, higher cochlear radiation doses, a history of smoking, and older age. With the rising incidence of this malignancy in Western countries and overall improved survivorship, our research motivates future studies into risk stratification and earlier interventions to mitigate and reduce the risk of ototoxicity. [ABSTRACT FROM AUTHOR]

Background: Aminoglycosides, such as Streptomycin, are cheap, potent antibiotics widely used Sub-Saharan Africa. However, aminoglycosides are the commonest cause of ototoxicity. The limited prospective epidemiological studies on aminoglycoside ototoxicity from Sub-Saharan Africa motivated this study to provide epidemiological information on Streptomycin-induced ototoxicity, identify risk factors and predictors of ototoxicity. Method: A longitudinal study of 153 adults receiving Streptomycin-based antituberculous drugs was done. All participants underwent extended frequency audiometry and had normal hearing thresholds at baseline. Hearing thresholds were assessed weekly for 2months, then monthly for the subsequent 6months. Ototoxicity was determined using the ASHA criteria. Descriptive statistics were used to analyze socio-demographic variables. Ototoxicity incidence rate was calculated, and Kaplan-Meier estimate used to determine cumulative probability of ototoxicity. Chi-square test was done to determine parameters associated with ototoxicity and Cox regression models were used to choose the predictors of ototoxicity. Results: Age of participants was 41.43 ± 12.66 years, with a male-to-female ratio of 1:0.6. Ototoxicity was found in 34.6% of the participants, giving an incidence of 17.26 per 1,000-person-week. The mean onset time to ototoxicity was 28.0 ± 0.47 weeks. By 28th week, risk of developing ototoxicity for respondents below 40 years of age was 0.29, and for those above 40 years was 0.77. At the end of the follow-up period, the overall probability of developing ototoxicity in the study population was 0.74. A significant difference in onset of ototoxicity was found between the age groups: the longest onset was seen in <40 years, followed by 40-49 years, and shortest onset in ≥50 years. Hazard of ototoxicity was significantly higher in participants aged ≥50 years compared to participants aged ≤40 years (HR = 3.76, 95% CI = 1.84-7.65). The probability of ototoxicity at 40 g, 60 g and 80 g cumulative dose of Streptomycin was 0.08, 0.43 and 2.34, respectively. Age and cumulative dose were significant predictors of ototoxicity. Conclusion: The mean onset time to Streptomycin-induced ototoxicity was 28 weeks after commencement of therapy. Age and cumulative dose can reliably predict the onset of Streptomycin-induced ototoxicity. Medium to long term monitoring of hearing is advised for patients on aminoglycoside therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the effect of intratympanic treatment with brain-derived neurotrophic factor embedded in collagen sponge and simultaneous oral administration of N-acetylcysteine (NAC) with amikacin on oxidative stress through glutathione peroxidase expression, audiological and histological changes in the cochlea of guinea pigs with ototoxicity caused by amikacin. MATERIALS AND METHODS: Fifty-five guinea pigs were included, in 50 ototoxicity occurred due to amikacin, they were divided into 5 groups of 10 animals each and were treated as follows: group I: without treatment, group II: post-hearing NAC, group III: simultaneous NAC-amikacin, group IV: saline solution and group V: brainderived neurotrophic factor. The animals were evaluated for 4 weeks with otoacoustic emissions by distortion products. Cochlear integrity was evaluated histologically and glutathione peroxidase production was evaluated immunohistochemically. Study was done from January 1st, 2022 to January 31, 2023. RESULTS: None of the animal reverted hearing loss. Histologically, groups I, II, III and IV showed severe loss of hair cells and mild in group V. In group I glutathione peroxidase production was severe; moderate in II, III and IV, and mild in V. CONCLUSIONS: Simultaneous and post-hearing loss treatment for NAC and intratympanic application of brain-derived neurotrophic factor do not prevent glutathione peroxidase production in guinea pigs with ototoxicity caused by amikacin, but they decrease it. [ABSTRACT FROM AUTHOR]

Background Aminoglycosides (AGs) are important antibiotics in the treatment of Gram-negative sepsis. However, they are associated with the risk of irreversible sensorineural hearing loss (SNHL). Several genetic variants have been implicated in the development of ototoxicity. Objectives To evaluate the pharmacogenetic determinants of AG-related ototoxicity. Methods This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and was registered on Prospero (CRD42022337769). In Dec 2022, PubMed, Cochrane Library, Embase and MEDLINE were searched. Included studies were those reporting original data on the effect of the AG-exposed patient's genome on the development of ototoxicity. Results Of 10 202 studies, 31 met the inclusion criteria. Twenty-nine studies focused on the mitochondrial genome, while two studied the nuclear genome. One study of neonates found that 30% of those with the m.1555A > G variant failed hearing screening after AG exposure (level 2 evidence). Seventeen additional studies found the m.1555A > G variant was associated with high penetrance (up to 100%) of SNHL after AG exposure (level 3–4 evidence). Nine studies of m.1494C > T found the penetrance of AG-related SNHL to be up to 40%; however, this variant was also identified in those with SNHL without AG exposure (level 3–4 evidence). The variants m.1005T > C and m.1095T > C may be associated with AG-related SNHL; however, further studies are needed. Conclusions This review found that the m.1555A > G and m.1494C > T variants in the MT-RNR1 gene have the strongest evidence in the development of AG-related SNHL, although study quality was limited (level 2–4). These variants were associated with high penetrance of a SNHL phenotype following AG exposure. [ABSTRACT FROM AUTHOR]

Objective: Teprotumumab plays an important role in thyroid eye disease pathogenesis and progression. We intend to mine the adverse event (AE) signals from a relevant database, thereby contributing to the safe use of teprotumumab. Methods: The data obtained from the ASCII data packages in the FAERS database from January 2020 to the second quarter of 2023 were imported into the SAS software (version 9.4) for data cleaning and analysis. Disproportionality analysis was performed using the reporting odds ratio (ROR) in conjunction with the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) omnibus standard method to detect positive signals. Participants: This retrospective observational study relied on adverse drug reactions reported to the FDA through FAERS, which is a standard public system for spontaneous reporting. Results: Collectively, 2171 AE reports for teprotumumab were collected, among which 108 significant signals were identified involving 17 system organ classes. The SOC of ear and labyrinth disorders included the most AE signals and reports. Muscle spasms, fatigue, headache, nausea, diarrhea, alopecia, blood glucose increased, hypoacusis, tinnitus, and diabetes mellitus were the top ten PTs ranked by the frequency of reporting, meanwhile, the two high-strength signals of thyroid-stimulating immunoglobulin increase (ROR 662.89, 95% CI 182.40–2409.19) and gingival recession (ROR 125.13, 95% CI 79.70–196.45) were not documented in the drug instruction. Meanwhile, we found a higher risk of increased blood glucose, deafness, and decreased appetite for male patients, and headache for female patients. Conclusions: Clinical application of teprotumumab should be closely monitored for ototoxicity, nail abnormalities, and menstrual changes, as well as for AEs not mentioned in the drug instruction, including gingival recession, thyroid-stimulating immunoglobulin increase, and so on. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cisplatin is an election chemotherapeutic agent used for many cancer treatments. Its cytotoxicity against neoplastic cells is mirrored by that taking place in healthy cells and tissues, resulting in serious adverse events. A very frequent one is ototoxicity, causing hearing loss which may permanently affect quality of life after successful oncologic treatments. Exacerbated oxidative stress is a main cytotoxic mechanism of cisplatin, including ototoxicity. Previous reports have shown antioxidant protection against cisplatin ototoxicity, but there is a lack of comparative studies on the otoprotectant activity and mechanism of antioxidant formulations. Here, we show evidence that a cocktail of vitamins A, C, and E along with Mg++ (ACEMg), previously shown to protect against noise-induced hearing loss, reverses auditory threshold shifts, promotes outer hair cell survival, and attenuates oxidative stress in the cochlea after cisplatin treatment, thus protecting against extreme cisplatin ototoxicity in rats. The addition of 500 mg N-acetylcysteine (NAC), which, administered individually, also shows significant attenuation of cisplatin ototoxicity, to the ACEMg formulation results in functional degradation of ACEMg otoprotection. Mg++ administered alone, as MgSO4, also prevents cisplatin ototoxicity, but in combination with 500 mg NAC, otoprotection is also greatly degraded. Increasing the dose of NAC to 1000 mg also results in dramatic loss of otoprotection activity compared with 500 mg NAC. These findings support that single antioxidants or antioxidant combinations, particularly ACEMg in this experimental series, have significant otoprotection efficacy against cisplatin ototoxicity. However, an excess of combined antioxidants and/or elevated doses, above a yet-to-be-defined "antioxidation threshold", results in unrecoverable redox imbalance with loss of otoprotectant activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Cisplatin-based chemoradiation is the standard of care for patients with squamous cell carcinomas of the head and neck area. Recent data from randomized phase 3 studies showed that weekly cisplatin has the same oncological outcomes as high-dose triweekly cisplatin when combined with definitive radiation. In this study, audiologic data were prospectively collected before, during, and after treatment completion. Standard audiogram evaluation was used in all cases. The primary endpoint was a hearing change grade of ≥3 (CTCAE v5.0) after completion of chemoradiation. The high-dose cisplatin regimen significantly increased the ≥grade 3 severe irreversible ototoxicity risk compared to the low-dose weekly regimen, irrespective of cumulative cisplatin dose, even with the use of cochlear-sparing intensity-modulated radiation therapy. No significant difference in oncologic outcomes was observed between the two schedules. These findings should be validated in a larger prospective multi-institutional study. Cisplatin, one of the most ototoxic anti-neoplastic agents, causes permanent hearing loss in up to 90% of patients. We assessed ototoxicity rates and prospectively collected audiologic outcomes of patients receiving low-dose or high-dose cisplatin with concurrent cochlear-sparing intensity-modulated radiation therapy (IMRT). Patients with head and neck squamous cell carcinoma (HNSCC) receiving definitive or adjuvant cisplatin-based chemoradiotherapy (CRT) were analyzed. Cisplatin was administered either in low doses weekly (40 mg/m2) for up to seven doses or in high doses triweekly (100 mg/m2) for up to three doses. Cochlear-sparing IMRT was delivered in all cases. Audiologic data were prospectively collected before, during, and after treatment completion. The primary endpoint was a hearing change grade of ≥3 after CRT completion. Of the 96 HNSCC patients evaluated, 69 received weekly cisplatin and 58 received definitive CRT. Of patients receiving weekly cisplatin, 13% developed ≥G3 ototoxicity vs. 56% of patients who received triweekly cisplatin (p < 0.001). In multivariable modeling, the cisplatin dose schedule remained significant (OR: 8.4, 95%CI: 2.8–27.8, p < 0.001) for risk of severe irreversible ototoxicity. Triweekly cisplatin CRT significantly increased the ≥G3 severe irreversible ototoxicity risk compared to low-dose weekly cisplatin, irrespective of the cumulative cisplatin dose, even with the use of cochlear-sparing IMRT. No significant difference in oncologic outcomes was observed between the two schedules. [ABSTRACT FROM AUTHOR]