Irreversible Sensorineural Hearing Loss Research Articles

Susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on sensory mechanoelectrical transduction channels both Ex Vivo and In Vivo

Cisplatin, a highly effective chemotherapeutic drug for various human cancers, induces irreversible sensorineural hearing loss as a side effect. Currently there are no highly effective clinical strategies for the prevention of cisplatin-induced ototoxicity. Previous studies have indicated that short-term cisplatin ototoxicity primarily affects the outer hair cells of the cochlea. Therefore, preventing the entry of cisplatin into hair cells may be a promising strategy to prevent cisplatin ototoxicity. This study aimed to investigate the entry route of cisplatin into mouse cochlear hair cells. The competitive inhibitor of organic cation transporter 2 (OCT2), cimetidine, and the sensory mechanoelectrical transduction (MET) channel blocker benzamil, demonstrated a protective effect against cisplatin toxicity in hair cells in cochlear explants. Sensory MET-deficient hair cells explanted from Tmc1Δ;Tmc2Δ mice were resistant to cisplatin toxicity. Cimetidine showed an additive protective effect against cisplatin toxicity in sensory MET-deficient hair cells. However, in the apical turn, cimetidine, benzamil, or genetic ablation of sensory MET channels showed limited protective effects, implying the presence of other entry routes for cisplatin to enter the hair cells in the apical turn. Systemic administration of cimetidine failed to protect cochlear hair cells from ototoxicity caused by systemically administered cisplatin. Notably, outer hair cells in MET-deficient mice exhibited no apparent deterioration after systemic administration of cisplatin, whereas the outer hair cells in wild-type mice showed remarkable deterioration. The susceptibility of mouse cochlear hair cells to cisplatin ototoxicity largely depends on the sensory MET channel both ex vivo and in vivo. This result justifies the development of new pharmaceuticals, such as a specific antagonists for sensory MET channels or custom-designed cisplatin analogs which are impermeable to sensory MET channels.

Exogenous humanin and MOTS-c function as protective agents against gentamicin-induced hair cell damage

Loss of hair cells can lead to irreversible sensorineural hearing loss. Therefore, hair cell preservation is critical for hearing. Mitochondrial derived peptides (MDPs) are bioactive peptides and prominent members of this family are humanin (HN) and the mitochondrial-open-reading frame of the twelve S c (MOTS-c). The protective roles of HN and MOTS-c in age-related diseases and in various tissues exposed to cellular stresses have been demonstrated. The involvement of MDPs in the inner ear remains to be investigated. Therefore, we determined the expression of rattin, the homolog of humanin, in inner ear tissues. Then, we found that HN and MOTS-c showed a significant protective effect on hair cells in organ of Corti explants exposed to gentamicin. Treatment with HN decreased gentamicin-induced phosphorylation of AKT, whereas treatment with MOTS-c increased phosphorylation of AMPKα in explants. Our data indicate that MDPs exert a protective function in gentamicin-induced hair cell damage. Therefore, MDPs may contribute to design new preventive strategies against hearing loss.

Irreversible Sensorineural Hearing Loss in Post Covid-19 Patients-An Institutional Prospective Study.

SARS-CoV-2 virus could damage the hearing by several mechanisms, it could damage the auditory centre in the temporal lobe and direct peripheral injury to the sensory cells of the cochlear due to neurotropism of the virus. A Prospective hospital-based observational study was carried out at a tertiary care centre for a period of 22months from January 2021 to October 2022. A total of 100 patients were selected according to inclusion criteria and exclusion criteria. Pure-tone audiometry (PTA) was done as a screening test; patients were followed up till 6months. Among those patients who had hearing loss, repeat audiological profile (PTA) was done after 1month, 13(65%) patients were found to have normal hearing. After 3months, repeat PTA was done, 18 patients (90%) found to have normal hearing and the remaining 2 patients followed up till 6months and again PTA was done where only 1 patient continued to have sensorineural hearing loss.

Aucubin protects mouse cochlear hair cells from cisplatin-induced ototoxicity via activation of the PI3K/AKT/STAT3 pathway

Cisplatin is commonly used to treat cancers and is associated with a significant risk of irreversible sensorineural hearing loss. However, no effective preventive strategies are available for cisplatin-induced HL. Therefore, significant efforts have been made to discover new drugs protecting cochlear hair cells from cisplatin-induced damage. We found that a new phytochemical, aucubin, attenuated cisplatin-induced apoptosis, the production of reactive oxygen species, and mitochondrial dysfunction in House Ear Institute Organ of Corti 1 cells and cochlear hair cells. Moreover, aucubin attenuated cisplatin-induced sensorineural hearing loss and hair cells loss in vivo. Furthermore, RNA sequencing analysis revealed that the otoprotective effects of aucubin were mainly mediated by increased STAT3 phosphorylation via the PI3K/AKT pathway. Inhibition of the STAT3 signaling pathway with the inhibitor S3I-201 or siRNA disrupted the protective effects of aucubin on cisplatin-induced apoptosis. In conclusion, we identified an otoprotective effect of aucubin. Therefore, aucubin could be used to prevent cisplatin-induced ototoxicity.

Transcriptomic Analysis of the Effect of Metformin against Cisplatin-Induced Ototoxicity: A Potential Mechanism of Metformin-Mediated Inhibition of Thioredoxin-Interacting Protein (Txnip) Gene Expression.

Ototoxicity is the drug-induced damage of the inner ear, causing bilateral irreversible sensorineural hearing loss. Cisplatin is a widely used chemotherapeutic agent which causes ototoxicity as its side effect. Pretreatment with metformin prior to the application of cisplatin significantly decreased the late apoptosis and attenuated the cisplatin-induced increase in ROS. To understand the molecular mechanisms that are involved in the preventive effect of metformin, we evaluated the change of gene expression induced by cisplatin at several different time points (0 h, 6 h, 15 h, 24 h and 48 h) and the alteration of gene expression according to pretreatment with metformin in HEI-OC1 cells through microarray analysis. Cisplatin exposure induced a total of 89 DEGs (differentially expressed genes) after 6 h, with a total of 433 DEGs after 15 h, a total of 941 DEGs after 24 h, and a total of 2764 DEGs after 48 h. When cells were pretreated with metformin for 24 h, we identified a total of 105 DEGs after 6 h of cisplatin exposure, a total of 257 DEGs after 15 h, a total of 1450 DEGs after 24 h, and a total of 1463 DEGs after 48 h. The analysis was performed based on the gene expression, network analyses, and qRT-PCR, and we identified several genes (CSF2, FOS, JUN, TNFα, NFκB, Txnip, ASK1, TXN2, ATF3, TP53, IL6, and IGF1) as metformin-related preventive biomarkers in cisplatin ototoxicity.

Noise Exposure and Hearing Health in the Workplace

Noise exposure is a potential occupational hazard found in almost every industrial sector.In Indonesia from research conducted on workers in workshops, wood industries and ferries, it was found that the noise intensity was between 85 – 103 dB and the prevalence of noise-induced hearing loss was between 21.7% - 34.5%. Besides being able to cause hearing loss, high-intensity noise also causes physical and psychological stress, interferes with communication and concentration, reduces work productivity, and even triggers work accidents. However, noise is often accepted as an unavoidable part of industrial processes causing workers to seem accustomed to noise and do not realize that it will gradually interfere with hearing and if left unchecked it can cause permanent / irreversible sensorineural hearing loss, so preventive measures are the best option to avoid hearing damage.

Modelling inner ear development and disease using pluripotent stem cells – a pathway to new therapeutic strategies

The sensory epithelia of the mammalian inner ear enable sound and movement to be perceived. Damage to these epithelia can cause irreversible sensorineural hearing loss and vestibular dysfunction because they lack regenerative capacity. The human inner ear cannot be biopsied without causing permanent damage, significantly limiting the tissue samples available for research. Investigating disease pathology and therapeutic developments have therefore traditionally relied on animal models, which often cannot completely recapitulate the human otic systems. These challenges are now being partly addressed using induced pluripotent stem cell-derived cultures, which generate the sensory epithelial-like tissues of the inner ear. Here, we review how pluripotent stem cells have been used to produce two-dimensional and three-dimensional otic cultures, the strengths and limitations of these new approaches, and how they have been employed to investigate genetic and acquired forms of audiovestibular dysfunction. This Review provides an overview of the progress in pluripotent stem cell-derived otic cultures thus far, focusing on their applications in disease modelling and therapeutic trials. We survey their current limitations and future directions, highlighting their prospective utility for high-throughput drug screening and developing personalised medicine approaches.

Polydatin activates the Nrf2/HO-1 signaling pathway to protect cisplatin-induced hearing loss in guinea pigs.

Irreversible sensorineural hearing loss is one of the most common side effects after cisplatin treatment. Prevention and reversal of hearing loss caused by cisplatin are of great importance for cancer patients, especially children. Oxidative stress is an important cause of hearing loss resulted from cisplatin, unfortunately, there is no drug yet available that can completely prevent and reverse the ototoxicity from cisplatin. Polydatin (PD) possesses excellent antioxidant and anti-inflammatory effects, however, its role in the cisplatin-induced hearing loss has not been investigated. Herein, we have explored the preventive and therapeutic effects of PD on cisplatin-induced hearing loss and the possible underlying mechanisms. In the in vivo setting with guinea pigs, we have demonstrated that PD can reduce the threshold shift of auditory brainstem response (ABR) caused by cisplatin, promote the nuclear translocation of Nuclear factor erythroid-2 related factor 2 (Nrf2), increase the expression of Nrf2 and heme oxygenase-1 (HO-1), and thus reduce the loss of outer hair cells (OHCs). PD can ameliorate cisplatin-induced hearing loss through activating the Nrf2/HO-1 signaling pathway. This study provides a potential strategy for preventing and improving hearing loss resulted from cisplatin treatment in clinics.

Osimertinib-induced hearing loss: an uncommon aftereffect of a novel drug—a case report

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have significantly improved survival outcomes of advanced non-small cell lung cancer (NSCLC). Nonetheless, usage of TKIs is not without adverse effects, as it has been reported to cause irreversible sensorineural hearing loss (SNHL).Case presentationWe describe a 72-year-old man who experienced hearing loss after taking osimertinib for 6 months. Later, his hearing further declined over a period of 1 year. Hearing rehabilitation with high-powered behind-the-ear (BTE) hearing aid has helped to improve his quality of life to some degree. There were no other known causative factors leading to the hearing deterioration. To date, there is no case report on osimertinib-induced SNHL.ConclusionPhysicians ought to counsel patients on osimertinib of this rare side effect and monitor for early signs of hearing loss. Treatment protocol should be in place taking into account that they have either failed or likely to fail the first- or second-line treatments and have advanced stage disease.

Understanding the Molecular Mechanism of Vestibular Schwannoma for Hearing Preservation Surgery: Otologists’ Perspective from Bedside to Bench

Vestibular schwannoma is a clinically benign schwannoma that arises from the vestibulocochlear nerve that causes sensorineural hearing loss. This tumor is clinically and oncologically regarded as a benign tumor as it does not metastasize or invade surrounding tissues. Despite being a benign tumor, its management is difficult and controversial due to the potential serious complications, such as irreversible sensorineural hearing loss, of current interventions. Therefore, preventing hearing loss due to the natural course of the disease and complications of surgery is a challenging issue for an otologist. Improvements have been reported recently in the treatment of vestibular schwannomas. These include advances in intraoperative monitoring systems for vestibular schwannoma surgery where the risk of hearing loss as a complication is decreased. Precise genomic analysis of the tumor would be helpful in determining the characteristics of the tumor for each patient, leading to a better hearing prognosis. These procedures are expected to help improve the treatment of vestibular schwannomas. This review summarizes recent advances in vestibular schwannoma management and treatment, especially in hearing preservation. In addition, recent advances in the understanding of the molecular mechanisms underlying vestibular schwannomas and how these advances can be applied in clinical practice are outlined and discussed, respectively. Moreover, the future directions from the bedside to the bench side are presented from the perspective of otologists.

Regulation of Spiral Ganglion Neuron Regeneration as a Therapeutic Strategy in Sensorineural Hearing Loss.

In the mammalian cochlea, spiral ganglion neurons (SGNs) are the primary neurons on the auditory conduction pathway that relay sound signals from the inner ear to the brainstem. However, because the SGNs lack the regeneration ability, degeneration and loss of SGNs cause irreversible sensorineural hearing loss (SNHL). Besides, the effectiveness of cochlear implant therapy, which is the major treatment of SNHL currently, relies on healthy and adequate numbers of intact SGNs. Therefore, it is of great clinical significance to explore how to regenerate the SGNs. In recent years, a number of researches have been performed to improve the SGNs regeneration strategy, and some of them have shown promising results, including the progress of SGN regeneration from exogenous stem cells transplantation and endogenous glial cells’ reprogramming. Yet, there are challenges faced in the effectiveness of SGNs regeneration, the maturation and function of newly generated neurons as well as auditory function recovery. In this review, we describe recent advances in researches in SGNs regeneration. In the coming years, regenerating SGNs in the cochleae should become one of the leading biological strategies to recover hearing loss.

Trehalose protects against cisplatin-induced cochlear hair cell damage by activating TFEB-mediated autophagy

Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors, but its side effects limit its application. Ototoxicity, a major adverse effect of cisplatin, causes irreversible sensorineural hearing loss. Unfortunately, there are no effective approaches to protect against this damage. Autophagy has been shown to exert beneficial effects in various diseases models. However, the role of autophagy in cisplatin-induced ototoxicity has been not well elucidated. In this study, we aimed to investigate whether the novel autophagy activator trehalose could prevent cisplatin-induced damage in the auditory cell line HEI-OC1 and mouse cochlear explants and to further explore its mechanisms. Our data demonstrated that trehalose alleviated cisplatin-induced hair cell (HC) damage by inhibiting apoptosis, attenuating oxidative stress and rescuing mitochondrial dysfunction. Additionally, trehalose significantly enhanced autophagy levels in HCs, and inhibiting autophagy with 3-methyladenine (3-MA) abolished these protective effects. Mechanistically, we showed that the effect of trehalose was attributed to increased nuclear translocation of transcription factor EB (TFEB), and this effect could be mimicked by TFEB overexpression and inhibited by TFEB gene silencing or treatment with cyclosporin A (CsA), a calcineurin inhibitor. Taken together, our findings suggest that trehalose and autophagy play a role in protecting against cisplatin-induced ototoxicity and that pharmacological enhancement of TFEB-mediated autophagy is a potential treatment for cisplatin-induced damage in cochlear HCs and HEI-OC1 cells.

P31 Cogan's syndrome—a neglected autoimmune vasculitis

P31 Cogan's syndrome—a neglected autoimmune vasculitis

Effect of cisplatin chemotherapy on the inner ear function and serum prestin concentration.

One of the main side effects of chemotherapy with cisplatin is irreversible sensorineural hearing loss. This study was conducted to assess the correlation between the serum prestin concentration as a potential cochlear biomarker and audiologic findings in patients after cisplatin chemotherapy. A total of 52 patients aged 18-75years were included in this prospective study. All the subjects were recruited from the radiotherapy and oncology center of a tertiary hospital in Rasht, Iran. Audiologic parameters evaluations and serum prestin concentrations were measured at baseline and after 1-3weeks of chemotherapy. The inner ear function was evaluated by pure-tone audiometry (PTA) and distortion product of otoacoustic emission (DPOAE). A repeated-measure analysis of variance was performed to evaluate the relationship between the PTA, DPOAE, serum prestin concentration and cumulative cisplatin dose. Fifty-two patients (36 females) participated in this study. The PTA results showed that ototoxicity was more frequent among the patients with a high cumulative dose of cisplatin (χ2 trend = 15.25; P < 0.001). DPOAE responses revealed that 38.5% of the patients had ototoxicity change after 40-80mg of cisplatin administration. After receiving 40-80mg of cisplatin, serum prestin concentration increased from 130 to 230pg/ml. There is a significant positive correlation between prestin concentration after receiving more than 80mg of cisplatin and the ototoxic changes in the DPOAE response. The present study showed correlations between prestin concentrations and ototoxicity diagnosis by DPOAE findings. An early rise in prestin concentration is particularly important and an early sign of hearing loss. Future studies are recommended to investigate the effect of varying doses of cisplatin on prestin concentration and any association between ototoxicity and clinicopathological features.

Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity

Cisplatin, the most widely used platinum-based anticancer drug, often causes progressive and irreversible sensorineural hearing loss in cancer patients. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. Nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin family and PARPs, has emerged as a potent therapeutic molecular target in various diseases. In our investigates, we observed that NAD+ level was changed in the cochlear explants of mice treated with cisplatin. Supplementation of a specific inhibitor (TES-1025) of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a rate-limiting enzyme of NAD+de novo synthesis pathway, promoted SIRT1 activity, increased mtDNA contents and enhanced AMPK expression, thus significantly reducing hair cells loss and deformation. The protection was blocked by EX527, a specific SIRT1 inhibitor. Meanwhile, the use of NMN, a precursor of NAD+ salvage synthesis pathway, had shown beneficial effect on hair cell under cisplatin administration, effectively suppressing PARP1. In vivo experiments confirmed the hair cell protection of NAD+ modulators in cisplatin treated mice and zebrafish. In conclusion, we demonstrated that modulation of NAD+ biosynthesis via the de novo synthesis pathway and the salvage synthesis pathway could both prevent ototoxicity of cisplatin. These results suggested that direct modulation of cellular NAD+ levels could be a promising therapeutic approach for protection of hearing from cisplatin-induced ototoxicity.

Mitophagy Impairment Aggravates Cisplatin-Induced Ototoxicity.

Cisplatin is an efficacious anticancer agent, but its use is limited by ototoxicity and resultant irreversible sensorineural hearing loss. Cisplatin ototoxicity is associated with cochlear cell oxidative stress and mitochondrial damage. However, mitophagy is vital for maintaining mitochondrial quality and cellular metabolism. Accordingly, we investigated the role of mitophagy in regulating cisplatin-induced ototoxicity using the auditory cell line HEI-OC1. In this study, HEI-OC1 cells were treated with either cisplatin alone (10 μM, 0, 8, 16, and 24 h); cisplatin (10 μM, 24 h) post transfection with small-interfering (si)RNAs targeting mitophagy-associated mRNAs; cisplatin (10 μM, 24 h) succeeding pretreatment with the mitophagy suppressor, 3-methyladenine (3-MA; 5 or 10 mM, 6 h); or cisplatin (30 μM, 24 h) following pretreatment with the mitophagy promoter, carbonyl cyanide m-chlorophenylhydrazone (CCCP; 1 or 2 μM, 2 h). The viability of cells, expression of mitophagy marker, and mitochondrial functions were then assessed in these cells. Cell viability was determined by a water-soluble tetrazolium assay; expression of mitophagy-associated proteins PINK1, Parkin, BNIP3, FUNDC1, p62, and LC3B was analyzed by Western blotting, mitochondrial membrane potential by flow cytometry, intracellular ATP by spectrophotometry, and mitochondrial degradation by dual staining for mitochondria and autophagosomes or lysosomes. Our results showed that cisplatin gradually reduced the viable cell number over time, induced mitochondrial depolarization, decreased intracellular ATP concentration, and enhanced the expression of PINK1, Parkin, BNIP3, p62, and LC3B. In addition, Parkin and BNIP3 knockdown accelerated cisplatin-induced loss of cell viability, mitochondrial membrane potential, mitophagosome/lysosome formation, and reduction in intracellular ATP production. Pretreatment with 3-MA aggravated the cisplatin-induced cytotoxicity, while that with CCCP reversed this effect. Overall, our findings indicate that mitophagy protects HEI-OC1 cells against cisplatin-induced cell death. Consequently, we strongly believe that targeted promotion of mitophagy may confer protection against cisplatin-induced ototoxicity.

A human induced pluripotent stem cell-based modular platform to challenge sensorineural hearing loss.

The sense of hearing depends on a specialized sensory organ in the inner ear, called the cochlea, which contains the auditory hair cells (HCs). Noise trauma, infections, genetic factors, side effects of ototoxic drugs (ie, some antibiotics and chemotherapeutics), or simply aging lead to the loss of HCs and their associated primary neurons. This results in irreversible sensorineural hearing loss (SNHL) as in mammals, including humans; the inner ear lacks the capacity to regenerate HCs and spiral ganglion neurons. SNHL is a major global health problem affecting millions of people worldwide and provides a growing concern in the aging population. To date, treatment options are limited to hearing aids and cochlear implants. A major bottleneck for development of new therapies for SNHL is associated to the lack of human otic cell bioassays. Human induced pluripotent stem cells (hiPSCs) can be induced in two‐dimensional and three‐dimensional otic cells in vitro models that can generate inner ear progenitors and sensory HCs and could be a promising preclinical platform from which to work toward restoring SNHL. We review the potential applications of hiPSCs in the various biological approaches, including disease modeling, bioengineering, drug testing, and autologous stem cell based‐cell therapy, that offer opportunities to understand the pathogenic mechanisms of SNHL and identify novel therapeutic strategies.

Protective Effects of Glucose-Related Protein 78 and 94 on Cisplatin-Mediated Ototoxicity.

Cisplatin is a widely used chemotherapeutic drug for treating various solid tumors. Ototoxicity is a major dose-limiting side effect of cisplatin, which causes progressive and irreversible sensorineural hearing loss. Here, we examined the protective effects of glucose-related protein (GRP) 78 and 94, also identified as endoplasmic reticulum (ER) chaperone proteins, on cisplatin-induced ototoxicity. Treating murine auditory cells (HEI-OC1) with 25 μM cisplatin for 24 h increased cell death resulting from excessive intracellular reactive oxygen species (ROS) accumulation and caspase-involved apoptotic signaling pathway activation with subsequent DNA fragmentation. GRP78 and GRP94 expression was increased in cells treated with 3 nM thapsigargin or 0.1 μg/mL tunicamycin for 24 h, referred to as mild ER stress condition. This condition, prior to cisplatin exposure, attenuated cisplatin-induced ototoxicity. The involvement of GRP78 and GRP94 induction was demonstrated by the knockdown of GRP78 or GRP94 expression using small interfering RNAs, which abolished the protective effect of mild ER stress condition on cisplatin-induced cytotoxicity. These results indicated that GRP78 and GRP94 induction plays a protective role in remediating cisplatin-ototoxicity.

Otosyphilis: A Review of the Literature.

The number of cases of syphilis has increased in the United States and in many high-income nations. Otosyphilis is a less recognized complication of syphilis that can lead to irreversible sensorineural hearing loss. Different pathophysiological mechanisms have been proposed to explain hearing loss in otosyphilis. We review the literature on otosyphilis in adults and propose the need for future work in this field to identify better ways to diagnose, treat, and manage this disease. Patients with syphilis should be screened routinely for hearing loss, and all patients with new, sudden, or fluctuating sensorineural hearing loss should be evaluated for syphilis.

Usefulness of Current Candidate Genetic Markers to Identify Childhood Cancer Patients at Risk for Platinum-Induced Ototoxicity: Results of the European PanCareLIFE Cohort Study

Background Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in the FDA drug label and a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. Methods: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, andACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. Findings: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at start of platinum treatment, cranial radiation, and the interaction term [platinum compound]*[cumulative dose of cisplatin]. Meta-analysis confirmed an allelic association of SLC22A2 rs316019 with cisplatin ototoxicity (odds ratio 1.46, 95% CI 1.10–1.95, p=0.009). Predictive performance of the genetic markers was poor, compared with the clinical risk factors. Interpretation: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, our study cannot recommend the use of any of the investigated genetic markers to guide the management and prevention of cisplatin-induced hearing loss. The study results will require a revision of the pharmacogenetic guideline and the FDA drug label. Funding Statement: This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 602030. CEK was funded by the Swiss Cancer Research Foundation (grant no. 4157-02-2017), the Swiss Cancer League (grant no. 3412-02-2014), the Bernese Cancer League, and the Lung League Bern. JFW received supplementary funding from the Danish Childhood Cancer Foundation and Soroptimist International Helsingor, Denmark. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The PanCareLIFE study has been approved by the local ethics committees: Kantonale Ethikkommission Bern, 362/2015; Comitate Etico Regionale, 507REG2014; Ethical Committee University Hospital Brno, June 11, 2016; Ethics Committee Fakultni Nemocnice v Motole, Prague; De Videnskabsetiske Komiteer Region Hovedstaden, H-1- 2014-125; Ethikkommission Medizinische Universitat Graz, 27-015 ex 14/15; Ethikkommission der Universitat Ulm, 160/17; Ethikkommission der Universitat zu Lubeck, 14/181; Ethik-Kommission der Arztekammer Westfalen-Lippe und der Westfalischen Wilhelms-Universitat Munster, 2014-619; Medische Ethische Toetsings Commissie Erasmus MC; Medisch Ethische Toetsingscommissie, 2015_202. The informed consent of the patient (if adult) or his/her legal representative has been obtained.