Inhibition of CISD1 attenuates cisplatin-induced hearing loss in mice via the PI3K and MAPK pathways.

Cisplatin is an effective chemotherapeutic drug for different cancers, but it also causes severe and permanent hearing loss. Oxidative stress and mitochondrial dysfunction in cochlear hair cells (HCs) have been shown to be important in the pathogenesis of cisplatin-induced hearing loss (CIHL). CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) plays a critical role in mitochondrial oxidative capacity and cellular bioenergetics. Targeting CISD1 may improve mitochondrial function in various diseases. However, the role of CISD1 in cisplatin-induced ototoxicity is unclear. Therefore, this study was performed to assess the role of CISD1 in cisplatin-induced ototoxicity. We found that CISD1 expression was significantly increased after cisplatin treatment in both HEI-OC1 cells and cochlear HCs. Moreover, pharmacological inhibition of CISD1 with NL-1 inhibited cell apoptosis and reduced mitochondrial reactive oxygen species accumulation in HEI-OC1 cells and cochlear explants. Inhibition of CISD1 with small interfering RNA in HEI-OC1 cells had similar protective effects. Furthermore, NL-1 protected against CIHL in adult C57 mice, as evaluated by the auditory brainstem response and immunofluorescent staining. Mechanistically, RNA sequencing revealed that NL-1 attenuated CIHL via the PI3K and MAPK pathways. Most importantly, NL-1 did not interfere with the antitumor efficacy of cisplatin. In conclusion, our study revealed that targeting CISD1 with NL-1 reduced reactive oxygen species accumulation, mitochondrial dysfunction, and apoptosis via the PI3K and MAPK pathways in HEI-OC1 cell lines and mouse cochlear explants in vitro, and it protected against CIHL in adult C57 mice. Our study suggests that CISD1 may serve as a novel target for the prevention of CIHL.

Establishing multifactorial risk factors for adult-onset hearing loss: A systematic review with topic modelling and synthesis of epidemiological evidence.

BACKGROUND: This systematic review explores the multifaceted nature of risk factors contributing to adult-onset HL. The objective was to synthesise the most recent epidemiological evidence to generate pooled proportional incidences for the identified risk factors. METHODS: We conducted an extensive search of electronic databases (MEDLINE, EMBASE, and psychINFO) for studies providing epidemiological evidence of risk factors associated with hearing loss. Topic modelling using Latent Dirichlet Allocation (LDA) was first conducted to determine how many risk factor themes were available from the papers. Data were analysed by calculating the pooled proportional incidence using a meta-analysis of proportions. RESULTS: From the 72 studies reviewed, six key risk factor themes emerged through LDA topic modelling. The review identified ototoxicity, primarily caused by cancer treatments and antibiotics, infectious diseases like COVID-19, occupational noise exposure, lifestyle factors, health conditions, biological responses, and age progression as significant risk factors for HL. The highest proportional incidence was found with cancer-related ototoxicity at 55.4% (95%CI: 39.0-70.7), followed closely by ototoxicity from infectious diseases at 50.0% (95%CI: 28.5-71.5). This high proportional incidence suggests the need to explore less destructive therapies and proactively monitor hearing function during treatments. CONCLUSIONS: The findings of this review, combined with the synthesis of epidemiological evidence, enhance our understanding of hearing loss (HL) pathogenesis and highlight potential areas for intervention, thereby paving the way for more effective prevention and management of adult-onset hearing loss in our ageing global population.

Priorities for hearing loss prevention and estimates of global cause-specific burdens of hearing loss: a systematic rapid review.

BACKGROUND: Hearing loss affects approximately 1·6 billion individuals worldwide. Many cases are preventable. We aimed to estimate the annual number of new hearing loss cases that could be attributed to meningitis, otitis media, congenital rubella syndrome, cytomegalovirus, and ototoxic medications, specifically aminoglycosides, platinum-based chemotherapeutics, and antimalarials. METHODS: We used a targeted and a rapid systematic literature review to calculate yearly global incidences of each cause of hearing loss. We estimated the prevalence of hearing loss for each presumed cause. For each cause, we calculated the global number of yearly hearing loss cases associated with the exposure by multiplying the estimated exposed population by the prevalence of hearing loss associated with the exposure, accounting for mortality when warranted. FINDINGS: An estimated 257·3 million people per year are exposed to these preventable causes of hearing loss, leading to an estimated 33·8 million new cases of hearing loss worldwide per year. Most hearing loss cases were among those with exposure to ototoxic medications (19·6 million [range 12·6 million-27·9 million] from short-course aminoglycoside therapy and 12·3 million from antimalarials). We estimated that 818 000 cases of hearing loss were caused by otitis media, 346 000 by meningitis, 114 000 by cytomegalovirus, and 59 000 by congenital rubella syndrome. INTERPRETATION: The global burden of preventable hearing loss is large. Hearing loss that is attributable to disease sequelae or ototoxic medications contributes substantially to the global burden of hearing loss. Prevention of these conditions should be a global health priority. FUNDING: The US National Institute on Deafness and Other Communication Disorders and the US National Institute on Aging.

CyberKnife Stereotactic Radiosurgery for Growing Vestibular Schwannoma: Longitudinal Tumor Control, Hearing Outcomes, and Predicting Post-Treatment Hearing Status.

OBJECTIVES: (1) To determine tumor control rates for treating growing vestibular schwannoma (VS) with CyberKnife stereotactic radiosurgery (CK SRS); (2) to determine hearing outcomes after CK SRS; (3) to propose a set of variables that could be used to predict hearing outcomes for patients receiving CK SRS for VS. STUDY DESIGN: Retrospective case series review. METHODS: 127 patients who received CK SRS for radiographically documented growing VS were reviewed. Tumors were monitored for post-procedure growth radiographically with linear measurements and three-dimensional segmental volumetric analysis (3D-SVA). Hearing outcomes were reviewed for 109 patients. Cox proportional hazard modeling was used to identify variables correlated with hearing outcomes. RESULTS: Tumor control rate was 94.5% for treating VS with CK SRS. Hearing outcomes were categorized using the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) classification system. As of their last available audiogram, 33.3% of patients with pre-treatment class A and 26.9% of patients with class B retained their hearing in that class. 15.3% of patients starting with class A or B with extended follow-up (>60 months), maintained hearing within this same grouping. Our final model proposed to predict hearing outcomes included age, fundal cap distance (FCD), tumor volume, and maximum radiation dose to the cochlea; however, FCD was the only statistically significant variable. CONCLUSION: CK SRS is an effective treatment for control of VS. Hearing preservation by class was achieved in a third of patients. Finally, FCD was found to be protective against hearing loss. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:S1-S12, 2024.

Puerarin inhibits cisplatin-induced ototoxicity in mice through regulation of TRPV1-dependent calcium overload.

Puerarin (PUE), a flavonoid derivative with vasodilatory effects found in the traditional Chinese medicine kudzu, has anti-sensorineural hearing loss properties. However, the mechanism of its protective effect against ototoxicity is not well understood. In this study, we used in vitro and in vivo methods to investigate the protective mechanism of puerarin against cisplatin (CDDP)-induced ototoxicity. We established an ototoxicity model of CDDP in BALB/c mice and assessed the degree of hearing loss and cochlear cell damage. We used bioinformatics analysis, molecular docking, histological analysis, and biochemical and molecular biology to detect the expression of relevant factors. Our results show that puerarin improved CDDP-induced hearing loss and reduced hair cell loss. It also blocked CDDP-induced activation of TRPV1 and inhibited activation of IP3R1 to prevent intracellular calcium overload. Additionally, puerarin blocked CDDP-stimulated p65 activation, reduced excessive ROS production, and alleviated cochlear cell apoptosis. Our study provides new evidence and potential targets for the protective effect of puerarin against drug-induced hearing loss. Puerarin ameliorates cisplatin-induced ototoxicity and blocks cellular apoptosis by inhibiting CDDP activated TRPV1/IP3R1/p65 pathway, blocking induction of calcium overload and excessive ROS expression.

Impact of the Mean Cochlear Biologically Effective Dose on Hearing Preservation After Stereotactic Radiosurgery for Vestibular Schwannoma: A Retrospective Longitudinal Analysis.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) is a useful alternative for small- to medium-sized vestibular schwannoma. To evaluate whether biologically effective dose (BED Gy2.47 ), calculated for mean (BED Gy2.47 mean) and maximal (BED Gy2.47 max) cochlear dose, is relevant for hearing preservation. METHODS: This is a retrospective longitudinal single-center study. Were analyzed 213 patients with useful baseline hearing. Risk of hearing decline was assessed for Gardner-Robertson classes and pure tone average (PTA) loss. The mean follow-up period was 39 months (median 36, 6-84). RESULTS: Hearing decline (Gardner-Robertson class) 3 years after SRS was associated with higher cochlear BED Gy2.47 mean (odds ratio [OR] 1.39, P = .009). Moreover, BED Gy2.47 mean was more relevant as compared with BED Gy2.47 max (OR 1.13, P = .04). Risk of PTA loss (continuous outcome, follow-up minus baseline) was significantly corelated with BED Gy2.47 mean at 24 (beta coefficient 1.55, P = .002) and 36 (beta coefficient 2.01, P = .004) months after SRS. Risk of PTA loss (>20 dB vs ≤) was associated with higher BED Gy2.47 mean at 6 (OR 1.36, P = .002), 12 (OR 1.36, P = .007), and 36 (OR 1.37, P = .02) months. Risk of hearing decline at 36 months for the BED Gy2.47 mean of 7-8, 10, and 12 Gy 2.47 was 28%, 57%, and 85%, respectively. CONCLUSION: Cochlear BED Gy2.47 mean is relevant for hearing decline after SRS and more relevant as compared with BED Gy2.47 max. Three years after SRS, this was sustained for all hearing decline evaluation modalities. Our data suggest the BED Gy2.47 mean cut-off of ≤8 Gy 2.47 for better hearing preservation rates .

Prevention and treatment of cisplatin-induced ototoxicity in adults: A systematic review.

OBJECTIVES: Ototoxicity is a common disabling side effect of platinum-based chemotherapy. This study aimed to assess the evidence on the management of platinum-induced ototoxicity in adult cancer patients. METHODS: Four databases were searched up to 1 November 2022. Original studies were included if they reported on a pharmacologic or non-pharmacologic intervention to prevent or treat platinum ototoxicity in adults. The articles' quality was assessed via two grading scales. RESULTS: Nineteen randomised controlled trials and five quasi-experimental studies with 1673 patients were analysed. Eleven interventions were identified, nine pharmacological and two non-pharmacological. Six of the interventions (sodium thiosulphate, corticoids, sertraline, statins, multivitamins and D-methionine) showed mild benefits in preventing cisplatin-induced ototoxicity. Only one trial assessed corticoids as a potential treatment. Overall, only six trials were deemed with a low risk of bias. The majority of studies inadequately documented intervention-related adverse effects, thereby limiting safety conclusions. CONCLUSIONS: Current interventions have mild benefits in preventing cisplatin-induced ototoxicity in adult cancer patients. Sodium thiosulphate is the most promising intervention as a preventive strategy. Rigorous, high-quality research is warranted, encompassing an evaluation of all potential symptoms and innovative treatment modalities.

Hear and Now: Ongoing Clinical Trials to Prevent Drug-Induced Hearing Loss.

Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet clinical need for therapies that protect against this hearing loss without reducing the therapeutic efficacy of these lifesaving drugs. At least 17 clinical trials evaluating 10 therapeutics are currently underway for therapies aimed at preventing aminoglycoside- and/or cisplatin-induced ototoxicity. This review describes the preclinical and clinical development of each of these approaches, provides updates on the status of ongoing trials, and highlights the importance of appropriate outcome measures in trial design and the value of reporting criteria in the dissemination of results.

The effects of treating GERD on the outcomes of otitis media with effusion: A systematic review and meta-analysis.

OBJECTIVE: Gastroesophageal reflux disease (GERD) may cause otitis media with effusion (OME). However, whether treating GERD can benefit patients with OME has not been well studied. METHODS: We systematically searched PubMed, Embase, Cochrane Library, and Wanfang databases. The search period was from the establishment of the databases until December 31, 2022. Clinical studies related to GERD treatment on the outcomes of OME were included. Two reviewers independently conducted literature screening and data extraction according to the inclusion and exclusion criteria. To evaluate the quality of the included studies, we used the NOS assessment tool and the RevMan 5.4. Subgroup analysis was conducted to reduce the risk of heterogeneity, and Egger and Begg funnel plots were used to evaluate publication bias. Meta-analysis was performed using Stata14.0 and Review Manager 5.4 software. RESULTS: Finally, 21,744 patients from 16 studies were included. The results showed that the rate of GERD in OME patients was 0.56 (95 % confidence interval (CI): 0.33, 0.79), while it was 0.04 (95 % CI: 0.03, 0.05) in the adult GERD population. The combined risk ratio (RR) of OME in patients with versus without GERD was 1.58 (95 % CI: 1.35, 1.85; p < 0.01). The efficacy rate of GERD treatment in OME patients was 0.59 (95 % CI: 0.44, 0.74), especially for those with chronic OME (0.64, 95 % CI: 0.36, 0.92). Compared to the control group, treatment with GERD improved the symptoms and efficacy of OME (OR = 1.65; 95 % CI: 0.95, 2.85; p > 0.05). The hearing loss cure rate was 0.70 (95 % CI: 0.57, 0.82). CONCLUSION: GERD has been suggested to be a high-risk factor for OME. Treatment of GERD can improve the symptoms of OME. However, further studies are required to verify these findings.

Dabrafenib protects from cisplatin-induced hearing loss in a clinically relevant mouse model.

The widely used chemotherapy cisplatin causes permanent hearing loss in 40%-60% of patients with cancer. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs are desperately needed. Here, we tested dabrafenib, an FDA-approved BRAF kinase inhibitor and anticancer drug, in a clinically relevant multidose cisplatin mouse model. The protective effects of dabrafenib, given orally twice daily with cisplatin, were determined by functional hearing tests and cochlear outer hair cell counts. Toxicity of the drug cotreatment was evaluated, and levels of phosphorylated ERK were measured. A dabrafenib dose of 3 mg/kg BW, twice daily, in mice, was determined to be the minimum effective dose, and it is equivalent to one-tenth of the daily FDA-approved dose for human cancer treatment. The levels of hearing protection acquired, 20-25 dB at the 3 frequencies tested, in both female and male mice, persisted for 4 months after completion of treatments. Moreover, dabrafenib exhibited a good in vivo therapeutic index (> 25), protected hearing in 2 mouse strains, and diminished cisplatin-induced weight loss. This study demonstrates that dabrafenib is a promising candidate drug for protection from cisplatin-induced hearing loss.

A Screening Platform for Hearing Loss and Cognitive Decline: WHISPER (Widespread Hearing Impairment Screening and PrEvention of Risk).

The WHISPER (Widespread Hearing Impairment Screening and PrEvention of Risk) platform was recently developed for screening for hearing loss (HL) and cognitive decline in adults. It includes a battery of tests (a risk factors (RF) questionnaire, a language-independent speech-in-noise test, and cognitive tests) and provides a pass/fail outcome based on the analysis of several features. Earlier studies demonstrated high accuracy of the speech-in-noise test for predicting HL in 350 participants. In this study, preliminary results from the RF questionnaire (137 participants) and from the visual digit span test (DST) (78 participants) are presented. Despite the relatively small sample size, these findings indicate that the RF and DST may provide additional features that could be useful to characterize the overall individual profile, providing additional knowledge related to short-term memory performance and overall risk of HL and cognitive decline. Future research is needed to expand number of subjects tested, number of features analyzed, and the range of algorithms (including supervised and unsupervised machine learning) used to identify novel measures able to predict the individual hearing and cognitive abilities, also including components related to the individual risk.

Berberine protects against neomycin-induced ototoxicity by reducing ROS generation and activating the PI3K/AKT pathway.

In mammals, aminoglycoside antibiotic-induced injury to hair cells (HCs) and associated spiral ganglion neurons (SGNs) is irreversible and eventually leads to permanent hearing loss. Efforts have been directed towards the advancement of efficacious therapeutic treatments to protect hearing loss, but the ideal substance for treating the damaged cochlear sensory epithelium has yet to be identified. Berberine (BBR), a quaternary ammonium hydroxide extracted from Coptis chinensis, has been found to display potential anti-oxidant and neuroprotective properties. However, its involvement in aminoglycoside antibiotic-induced ototoxicity has yet to be explored or assessed. In the present study, we explored the possible anti-oxidative properties of BBR in mitigating neomycin-triggered ototoxicity. An improved survival of HCs and SGN nerve fibers (NFs) in organ of Corti (OC) explants after neomycin with BBR co-treatment was observed, and BBR treatment attenuated reactive oxygen species (ROS) generation and reduced cleaved caspase-3 signaling by activating six phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling relative subtypes, and the addition of PI3K/AKT suppressor LY294002 resulted in a decrease in the protective effect. The protective effect of BBR against ototoxicity was also evident in a neomycin-injured animal model, as evidenced by the preservation of HC and SGN in mice administered subcutaneous BBR for 7 days. In summary, all results suggest that BBR has potential as a new and effective otoprotective agent, operating via the PI3K/AKT signaling pathway.

Preclinical prospects of investigational agents for hearing loss treatment.

INTRODUCTION: : Hearing loss has a high prevalence, with aging, noise exposure, ototoxic drug therapies, and genetic mutations being some of the leading causes of hearing loss. Health conditions such as cardiovascular disease and diabetes are associated with hearing loss, perhaps due to shared vascular pathology in the ear and in other tissues. AREAS COVERED: : Issues in the design of preclinical research preclude the ability to make comparisons regarding the relative efficacy of different drugs of interest for possible hearing loss prevention or hearing restoration. This has not slowed the advancement of candidate therapeutics into human clinical testing. There is a robust pipeline with drugs that have different mechanisms of action providing diverse candidate therapies and opportunities for combination therapies to be considered. EXPERT OPINION: : Much of the preclinical research literature lacks standard study design elements such as dose response testing, and lack of standardization of test protocols significantly limits conclusions regarding relative efficacy. Nonetheless, the many positive results to date have supported translation of preclinical efforts into clinical trials assessing potential human benefits. Approval of the first hearing loss prevention therapeutic is a major success, providing a pathway for other drugs to follow.

Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial.

BACKGROUND: Hearing loss is associated with increased cognitive decline and incident dementia in older adults. We aimed to investigate whether a hearing intervention could reduce cognitive decline in cognitively healthy older adults with hearing loss. METHODS: The ACHIEVE study is a multicentre, parallel-group, unmasked, randomised controlled trial of adults aged 70-84 years with untreated hearing loss and without substantial cognitive impairment that took place at four community study sites across the USA. Participants were recruited from two study populations at each site: (1) older adults participating in a long-standing observational study of cardiovascular health (Atherosclerosis Risk in Communities [ARIC] study), and (2) healthy de novo community volunteers. Participants were randomly assigned (1:1) to a hearing intervention (audiological counselling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed up every 6 months. The primary endpoint was 3-year change in a global cognition standardised factor score from a comprehensive neurocognitive battery. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, NCT03243422. FINDINGS: From Nov 9, 2017, to Oct 25, 2019, we screened 3004 participants for eligibility and randomly assigned 977 (32·5%; 238 [24%] from ARIC and 739 [76%] de novo). We randomly assigned 490 (50%) to the hearing intervention and 487 (50%) to the health education control. The cohort had a mean age of 76·8 years (SD 4·0), 523 (54%) were female, 454 (46%) were male, and most were White (n=858 [88%]). Participants from ARIC were older, had more risk factors for cognitive decline, and had lower baseline cognitive scores than those in the de novo cohort. In the primary analysis combining the ARIC and de novo cohorts, 3-year cognitive change (in SD units) was not significantly different between the hearing intervention and health education control groups (-0·200 [95% CI -0·256 to -0·144] in the hearing intervention group and -0·202 [-0·258 to -0·145] in the control group; difference 0·002 [-0·077 to 0·081]; p=0·96). However, a prespecified sensitivity analysis showed a significant difference in the effect of the hearing intervention on 3-year cognitive change between the ARIC and de novo cohorts (pinteraction=0·010). Other prespecified sensitivity analyses that varied analytical parameters used in the total cohort did not change the observed results. No significant adverse events attributed to the study were reported with either the hearing intervention or health education control. INTERPRETATION: The hearing intervention did not reduce 3-year cognitive decline in the primary analysis of the total cohort. However, a prespecified sensitivity analysis showed that the effect differed between the two study populations that comprised the cohort. These findings suggest that a hearing intervention might reduce cognitive change over 3 years in populations of older adults at increased risk for cognitive decline but not in populations at decreased risk for cognitive decline. FUNDING: US National Institutes of Health.

Curcumin protects against the age-related hearing loss by attenuating apoptosis and senescence via activating Nrf2 signaling in cochlear hair cells.

Age-related hearing loss (ARHL) is a most widespread neurodegenerative disease affecting the elderly population, but effective pharmacological treatments remain limited. Curcumin is a bioactive compound of Curcuma longa with antioxidant properties. Herein, we looked into the effects of curcumin on the H2O2-induced oxidative stress in cochlear hair cells and hearing function in an ARHL animal model (C57BL/6J mice). We found that pretreatment of curcumin could attenuate H2O2-induced apoptosis and cell senescence in auditory hair cells and prevent mitochondrial function dysfunction. More specifically, Western blot and luciferase activity assay showed that curcumin activated the nuclear translocation of Nrf2, which in turn triggered the activation of its downstream target gene Heme Oxygenase1 (HO-1). The enhanced Nrf2 and HO-1 activity by curcumin was blocked by the AKT inhibitor LY294002, indicating the protective effect of curcumin was mainly achieved by activating Nrf2/HO-1 through the AKT pathway. Furthermore, the knockdown of Nrf2 with siRNA diminished the protective effects of Nrf2 against apoptosis and senescence, consolidating the pivotal role of Nrf2 in the protective effect of curcumin on auditory hair cells. More importantly, curcumin (10 mg/kg/d) could attenuate progressive hearing loss in C57BL/6J mice, as evident from the reduced threshold of auditory nerve brainstem response. Administration of curcumin also elevated the expression of Nrf2 and reduced the expression of cleaved-caspase-3, p21, and γ-H2AX in cochlear. This study is the first to demonstrate that curcumin can prevent oxidative stress-induced auditory hair cell degeneration through Nrf2 activation, highlighting its potential therapeutic value in preventing ARHL.

Safety of antituberculosis agents used for multidrug-resistant tuberculosis among patients attending the Jamot Hospital of Yaounde, Cameroon.

Background: Recognized in 1994 as a global emergency by the World Health Organization, tuberculosis (TB) remains an ongoing health threat. In Cameroon, the mortality rate is estimated at 2.9%. Treatment of multidrug-resistant TB (MDR-TB) defined as the resistance to the two most effective antiTB drugs, and requires therapy of more than 7 drugs taken on a daily basis during 9-12 months. This study aimed to evaluate the safety profile of treatment regimens used for MDR-TB at Jamot Hospital of Yaounde (JHY). Methods: This was a retrospective cohort study of patients treated for MDR-TB at HJY from January 1, 2017, to December 31, 2019. Patients characteristics of the cohort, drugs regimen were collected and described. All possible adverse drug reactions (ADR) were described clinically and by severity grade. Results: During the study period, 107 patients were included, and 96 (89.7%) experienced at least one ADR. Most parts of the patients (90) experienced mild or moderate ADR. Hearing loss was the most frequent ADR, and led mostly in aminoglycosides dose reduction (n = 30, 96.7%). Gastrointestinal events were commonly observed during the study period. Conclusion: Our findings suggested that ototoxicity was a prominent safety issue during the study period. The implementation of the new short treatment regimen could be effective in reducing the burden of ototoxicity among MDR-TB patients. Nevertheless, new safety issues could emerge.

Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial.

PURPOSE: Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL. PATIENTS AND METHODS: In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations. RESULTS: Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021-0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011-0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection. CONCLUSIONS: NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.

Do hearing loss interventions prevent dementia?

Hearing loss has been identified as a potentially modifiable risk for dementia. This discussion paper reviews studies examining the impact of hearing loss interventions on cognitive decline and incident cognitive impairment, identified the challenges for research on the cognitive impacts of hearing interventions, and the likely benefits of hearing interventions for healthy aging and mental well-being.