The Relationship Between Cisplatin-related and Age-related Hearing Loss During an Extended Follow-up.

OBJECTIVES: Cisplatin-related hearing loss (HL) is claimed to progress after treatment. This controlled longitudinal study with extended follow-up investigates HL in testicular cancer survivors (TCSs) after cisplatin-based chemotherapy (CBCT). STUDY DESIGN: Controlled longitudinal study. METHODS: Eighty-two TCSs treated with CBCT between 1980 and 1994 in Norway participated in two surveys (S1/S3), including pure-tone audiograms (0.125-8 kHz) and self-reported HL, 12 and 31 years after treatment, respectively. Hearing thresholds were age-adjusted based on age-matched hearing thresholds from the general population (controls). Hearing loss was defined as thresholds >20 dB at any frequency. RESULTS: Between the two surveys, the prevalence of high-frequency HL (4, 6, and 8 kHz) increased from 73% to 94% but approached those of the aging general population after age adjustment. In TCSs aged >40 years at first survey, HL at the subsequent survey equaled that of controls. Self-reported HL increased from seven (9%) at S1 to 20 (26%) at S3. At S1, age-adjusted HL was identified in all (seven) TCSs reporting decreased hearing whereas at S3, hearing thresholds did not differ from controls in seven out of 20 patients reporting HL. CONCLUSION: CBCT-related ototoxicity causes high-frequency HL, but in contrast to reports from follow-up studies from the first post-treatment decade, no major progression was found beyond the first post-treatment decade for frequencies 0.125-8 kHz. Importantly, with extended follow-up, hearing thresholds of patients approach those of the general population, possibly due to a less-than-additive effect with age-related hearing loss (ARHL) in CBCT-treated patients. Age-and sex-matching is strongly advised in long-term follow-up of CBCT-related ototoxicity. Specificity for detecting ototoxicity with self-reported questionnaires decreases with extended follow-up. LEVEL OF EVIDENCE: 3 Laryngoscope, 130:E515-E523, 2020.

Neuronal erythropoietin overexpression is protective against kanamycin-induced hearing loss in mice.

Aminoglycosides have detrimental effects on the hair cells of the inner ear, yet these agents indisputably are one of the cornerstones in antibiotic therapy. Hence, there is a demand for strategies to prevent aminoglycoside-induced ototoxicity, which are not available today. In vitro data suggests that the pleiotropic growth factor erythropoietin (EPO) is neuroprotective against aminoglycoside-induced hair cell loss. Here, we use a mouse model with EPO-overexpression in neuronal tissue to evaluate whether EPO could also in vivo protect from aminoglycoside-induced hearing loss. Auditory brainstem response (ABR) thresholds were measured in 12-weeks-old mice before and after treatment with kanamycin for 15 days, which resulted in both C57BL/6 and EPO-transgenic animals in a high-frequency hearing loss. However, ABR threshold shifts in EPO-transgenic mice were significantly lower than in C57BL/6 mice (mean difference in ABR threshold shift 13.6 dB at 32 kHz, 95% CI 3.8-23.4 dB, p = 0.003). Correspondingly, quantification of hair cells and spiral ganglion neurons by immunofluorescence revealed that EPO-transgenic mice had a significantly lower hair cell and spiral ganglion neuron loss than C57BL/6 mice. In conclusion, neuronal overexpression of EPO is protective against aminoglycoside-induce hearing loss, which is in accordance with its known neuroprotective effects in other organs, such as the eye or the brain.

Intrathecal 2-hydroxypropyl-ß-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.

BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-ß-cyclodextrins (HPßCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPßCD. METHODS: In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPßCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPßCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPßCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. FINDINGS: Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPßCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPßCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPßCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423). INTERPRETATION: Patients with NPC1 treated with intrathecal HPßCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPßCD. FUNDING: National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.

Hearing and Vestibular Function After Preoperative Intratympanic Gentamicin Therapy for Vestibular Schwanomma as Part of Vestibular Prehab.

OBJECTIVE: To evaluate auditory and vestibular function after presurgical treatment with gentamicin in schwannoma patients. BACKGROUND: The vestibular PREHAB protocol aims at diminishing the remaining vestibular function before vestibular schwannoma surgery, to ensure less acute symptoms from surgery, and initiate a more efficient vestibular rehabilitation already before surgery. However, the potential cochleotoxicity of gentamicin is a concern, since modern schwannoma surgery strives to preserve hearing. STUDY DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Seventeen patients diagnosed with vestibular schwannoma between 2004 and 2011, and took part in vestibular PREHAB program. The patients were of age 21 to 66 years (mean 48.8), 9 females and 8 males. INTERVENTION: Intratympanic gentamicin installations before surgery as part of the vestibular PREHAB. MAIN OUTCOME MEASURES: Hearing thresholds, word recognition score, caloric response, subjective visual vertical and horizontal, cVEMP, and vestibular impulse tests. RESULTS: Combined analysis of frequency and hearing threshold showed a significant decrease after gentamicin therapy (p < 0.001). Pure-tone average decreased with 7.1 ± 8.5 dB (p = 0.004), and speech recognition with 10%. The treatment resulted in unilateral vestibular deafferentation with no notable reaction to bithermal caloric irrigation (reduction 64%, p < 0.001), loss of the vestibulo-ocular response measured by the head-impulse test, and deviation of subjective horizontal/vertical to the side of the lesion (+2.2 degrees, p = 0.010). CONCLUSIONS: Intratympanic installations of gentamicin, as part of the vestibular PREHAB, result in unilateral vestibular deafferentation, but constitute a definite risk for high-frequency hearing loss. The hearing results are in line with those reported upon when treating Menière's disease.

XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death.

Here we study links between aminoglycoside-induced mistranslation, protein misfolding and neuropathy. We demonstrate that aminoglycosides induce misreading in mammalian cells and assess endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways. Genome-wide transcriptome and proteome analyses revealed upregulation of genes related to protein folding and degradation. Quantitative PCR confirmed induction of UPR markers including C/EBP homologous protein, glucose-regulated protein 94, binding immunoglobulin protein and X-box binding protein-1 (XBP1) mRNA splicing, which is crucial for UPR activation. We studied the effect of a compromised UPR on aminoglycoside ototoxicity in haploinsufficient XBP1 (XBP1(+/-)) mice. Intra-tympanic aminoglycoside treatment caused high-frequency hearing loss in XBP1(+/-) mice but not in wild-type littermates. Densities of spiral ganglion cells and synaptic ribbons were decreased in gentamicin-treated XBP1(+/-) mice, while sensory cells were preserved. Co-injection of the chemical chaperone tauroursodeoxycholic acid attenuated hearing loss. These results suggest that aminoglycoside-induced ER stress and cell death in spiral ganglion neurons is mitigated by XBP1, masking aminoglycoside neurotoxicity at the organismal level.

A guinea pig model of selective severe high-frequency hearing loss.

HYPOTHESIS: Using an appropriate dose of an aminoglycoside antibiotic cotreated with a loop diuretic a guinea pig model of high-frequency loss can be obtained mimicking cochlear implant candidates with low-frequency residual hearing. We examined the stability of this model over time. BACKGROUND: A well-established method to create an animal model for profound deafness is cotreatment with an aminoglycoside antibiotic and a loop diuretic. Recent data indicated that reduction of the aminoglycoside dose might yield selective high-frequency hearing loss. Such a model is relevant for studies related to hybrid cochlear implant devices, for example, with respect to preservation of residual hearing. METHODS: Guinea pigs received an electrode for chronic recording of compound action potentials to tones to assess thresholds. They were treated with a coadministration of kanamycin (200 mg/kg) and furosemide (100 mg/kg), after which, the animals were sacrificed for histologic analysis at 2, 4, or 7 weeks. RESULTS: After 2 to 7 weeks threshold shifts were greater than 50 dB for 8 to 16 kHz in 15 of 17 animals, whereas threshold shifts at 2 kHz or lower were less than 50 dB in 13 animals. Major threshold shifts occurred the first 2 to 4 days; subsequently, some spontaneous recovery occurred and, after 2-3 weeks thresholds, remained stable. Inner hair cell loss still progressed between 2 and 4 weeks in the most basal cochlear region; thereafter, hair cell loss was stable. CONCLUSION: An appropriate animal model for selective severe high-frequency hearing loss was obtained, which is stable at 4 weeks after ototoxic treatment.

Spatial overlap of combined electroacoustic stimulation determines the electrically evoked response in the guinea pig cochlea.

HYPOTHESIS: Limiting spatial overlap between electrical stimulation (ES) and acoustical stimulation (AS) in the cochlea reduces the effects of AS on electrically evoked auditory nerve activity. BACKGROUND: Some hybrid cochlear implant systems have a regular array, whereas others have short arrays that spatially segregate ES from AS. AS settings in hybrid implants may also affect electroacoustic interaction. METHODS: ES (900 µA) was delivered in the high-frequency part of the cochlea, and the electrically evoked compound action potential (eCAP) was recorded to assess auditory nerve activity. Maximal spatial overlap of ES and AS was tested by using normal-hearing animals (NH, n = 6), whereas minimal overlap was modeled by using animals with high-frequency hearing loss (HFHL, n = 6). AS consisted of broadband (BB) or low-frequency (LF) noise (0-100 dB SPL). Effects of AS on eCAP amplitude were statistically tested using 1-sample t tests (α = 0.05). RESULTS: BB noise at 60 dB SPL significantly suppressed eCAP amplitude in NH animals but not in HFHL animals up to a 30 dB higher level. Suppression with LF noise at 60 dB SPL was not significant in either the NH or the HFHL group, but at 90 dB SPL, suppression was significant in both groups. CONCLUSION: Minimizing spatial overlap between ES and AS reduces eCAP suppression when moderate sound levels are applied. Overlap can be reduced by applying ES in an acoustically insensitive part of the cochlea or by limiting the acoustic spectrum to low frequencies when ES is applied in acoustically sensitive areas.

"Accelerated ear-age": a new measure of chemotherapy-induced ototoxicity.

Currently, there are several different scales that grade chemotherapy-induced ototoxicity. This report highlights how the implications of the conclusions drawn from each scale differ and compare these prior scales to a more functionally based scale developed at Children's Hospital Boston. Additionally, this report introduces the concept of "ear-age," akin to the age at which one would expect the observed decrease in hearing as a consequence of normative aging (but documented in a child or young adult following chemotherapy).

Progressive hearing loss after completion of cisplatin chemotherapy is common and more pronounced in children without spontaneous otoacoustic emissions before chemotherapy.

OBJECTIVE: High frequency hearing loss following cisplatin chemotherapy is frequent in children and often necessitates the fitting of hearing aids. During therapy, hearing is usually monitored. Post-therapeutic follow-up does not routinely include monitoring of hearing, although there are indications that hearing thresholds can decline after therapy. METHODS: Pure-tone audiograms taken from 27 children (17 males, 10 females) treated with cisplatin at Muenster university hospital (mean age 9.84 years, standard deviation 3.67 years) including an audiological follow-up at least 6 months after therapy, were analyzed retrospectively. RESULTS: In follow-up tests after completion of therapy, 24.1% of all ears showed an increase in mean high frequency hearing thresholds (4-8 kHz). Post-therapeutic hearing deterioration was significant at 4 kHz and significantly more pronounced in children without measurable spontaneous otoacoustic emissions (SOAE) before therapy. Post-therapeutic hearing deterioration did not occur in ears with normal pure tone thresholds (≤ 10dB at all frequencies) after cisplatin therapy. No correlation was found between post-therapeutic hearing deterioration and cranial irradiation. CONCLUSIONS: Cisplatin chemotherapy follow-up should include audiological monitoring in all children with elevated pure tone thresholds after therapy. Routine SOAE measurements taken as part of baseline audiometry before the start of chemotherapy can be taken into consideration.

Effects of electrical stimulation on the acoustically evoked auditory-nerve response in guinea pigs with a high-frequency hearing loss.

Criteria for cochlear implantation keep expanding and people with substantial residual low-frequency hearing are considered candidates for implantation nowadays. Therefore, electro-acoustical stimulation in the same ear (EAS) is receiving increasing interest. We have investigated the effects of intracochlear electrical stimulation on acoustically evoked auditory-nerve activity, using a forward masking paradigm. The stimulation electrode was placed in the basal turn of the cochlea. Compound action potential (CAP) recordings were performed in guinea pigs with severe high-frequency hearing loss and in normal-hearing control animals. In normal-hearing animals, electrical stimulation generally suppressed CAPs, especially at high acoustic frequencies (8 and 16 kHz) and low sound levels. At low frequencies (0.5 and 1 kHz), suppression was observed only at high sound levels. In animals with a high-frequency hearing loss, suppression of CAPs at low frequencies was substantially less compared to control animals, even at high current levels and temporal overlap of acoustic and electric stimuli. Hence, effects of electrical stimulation substantially differed between normal-hearing animals and animals with a high-frequency hearing loss. These findings stress the need for a proper animal model when investigating EAS. We conclude that in case of high-frequency loss, the basal part of the cochlea can be stimulated electrically with little effect on responses to low-frequency acoustic stimuli.

ENU induced single mutation locus on chr 16 leads to high-frequency hearing loss in mice.

The hallmark of age-related (presbycusis) and noise-induced hearing loss is high-frequency (> 20 kHz) hearing loss. Through a collaborative study with TMGC (Tennessee Mouse Genome Consortium), seventeen ENU-induced mouse mutation strains with high-frequency hearing loss have been identified, but affected genes are yet identified. As a first step in identifying the gene/s underlying the ENU mutations, we created a F2 population between a representative mutation strain, 118 TNE and a wild type strain, CAST/EJ (CAST). Phenotypic analysis showed that there is a 3:1 ratio of segregation between normal and hearing loss in the F2 population, suggestion a single locus regulation. However, the linkage mapping identified 2 QTLs, each on chromosomes 15 and 16. Further statistical analysis of marker segregation patterns revealed that the locus on Chr 16 was ENU induced while the one on Chr 15 was derived from the parental strain, CAST.

Effects of neonatal partial deafness and chronic intracochlear electrical stimulation on auditory and electrical response characteristics in primary auditory cortex.

The use of cochlear implants in patients with severe hearing losses but residual low-frequency hearing raises questions concerning the effects of chronic intracochlear electrical stimulation (ICES) on cortical responses to auditory and electrical stimuli. We investigated these questions by studying responses to tonal and electrical stimuli in primary auditory cortex (AI) of two groups of neonatally deafened cats with residual high-threshold, low-frequency hearing. One group were implanted with a multi-channel intracochlear electrode at 8 weeks of age, and received chronic ICES for up to 9 months before cortical recording. Cats in the other group were implanted immediately prior to cortical recording as adults. In all cats in both groups, multi-neuron responses throughout the rostro-caudal extent of AI had low characteristic frequencies (CFs), in the frequency range of the residual hearing, and high-thresholds. Threshold and minimum latency at CF did not differ between the groups, but in the chronic ICES animals there was a higher proportion of electrically but not acoustically excited recording sites. Electrical response thresholds were higher and latencies shorter in the chronically stimulated animals. Thus, chronic implantation and ICES affected the extent of AI that could be activated by acoustic stimuli and resulted in changes in electrical response characteristics.

High frequency audiometric study in cancer-cured patients treated with cisplatin.

UNLABELLED: Hearing loss has been described in patients undergoing chemotherapy, given the ototoxic nature of these drugs. An audiological investigation is relevant in such cases. AIM: to assess audibility thresholds at high frequencies in individuals with cancer that was treated successfully with cisplatin and its associations, to verify possible hearing loss as a side effect of therapy. Site and date of the study: Campinas, Sao Paulo, in 2006. MATERIAL AND METHOD: Ten volunteers aged between 5 and 27 years were assessed by a clinical history, otoscopy, and conventional and high frequencies audiometry in this clinical and experimental study. RESULTS: A kappa coefficient statistical analysis revealed significant differences between ears in 50% of 14 frequencies that were evaluated. Eight participants presented hearing losses, which started at 1 kHz, increasing markedly at 6 kHz and above. Fisher's Exact Test revealed a significant association only with the dose and the right ear at high frequencies. CONCLUSION: It is possible that the hearing loss detected in this study is at least partially due to the ototoxicity of antineoplastic drugs; such loss may occur even after treatment is interrupted. We suggest that a protocol for audiological follow-up of patients undergoing chemotherapy should be created.

Estudo audiometrico de alta fraquência em pacientes curados de câncer tratados com cisplatina / High frequency audiometric study in cancer-cured patients treated with cisplatin

Alterações auditivas têm sido encontradas em pacientes submetidos à quimioterapia devido à ototoxicidade, daí a importância da investigação audiológica nesses casos. OBJETIVO: Avaliar os limiares de audibilidade nas altas freqüências em indivíduos curados de câncer, tratados com cisplatina e associações, para verificar possível perda auditiva como seqüela do tratamento. Local e data do estudo: Campinas - SP, em 2006. MATERIAL E MÉTODO: Roteiro de anamnese, otoscópio e audiômetro. Dez voluntários, entre 5 a 27 anos, foram submetidos a anamnese; meatoscopia; audiometria tonal convencional e de altas freqüências. Forma de Estudo: Clínico experimental. RESULTADOS: O kappa ponderado evidenciou diferença significativa entre as orelhas em 50 por cento das 14 freqüências avaliadas. Oito participantes apresentaram perda auditiva. O acometimento iniciou-se em 1 kHz, com crescimento acentuado a partir de 6kHz. O Teste Exato de Fisher evidenciou associação significativa apenas para dose e orelha direita nas altas freqüências. CONCLUSÃO: É possível que as perdas auditivas detectadas devam-se, pelo menos parcialmente, à ototoxicidade dos antineoplásicos utilizados, a qual pode ocorrer mesmo após a interrupção do tratamento. Sugere-se estabelecer protocolo de acompanhamento audiológico no tratamento quimioterápico.

Hearing loss has been described in patients undergoing chemotherapy, given the ototoxic nature of these drugs. An audiological investigation is relevant in such cases. AIM: to assess audibility thresholds at high frequencies in individuals with cancer that was treated successfully with cisplatin and its associations, to verify possible hearing loss as a side effect of therapy. Site and date of the study: Campinas, Sao Paulo, in 2006. MATERIAL AND METHOD: Ten volunteers aged between 5 and 27 years were assessed by a clinical history, otoscopy, and conventional and high frequencies audiometry in this clinical and experimental study. RESULTS: A kappa coefficient statistical analysis revealed significant differences between ears in 50 percent of 14 frequencies that were evaluated. Eight participants presented hearing losses, which started at 1 kHz, increasing markedly at 6 kHz and above. Fisher's Exact Test revealed a significant association only with the dose and the right ear at high frequencies. CONCLUSION: It is possible that the hearing loss detected in this study is at least partially due to the ototoxicity of antineoplastic drugs; such loss may occur even after treatment is interrupted. We suggest that a protocol for audiological follow-up of patients undergoing chemotherapy should be created.

Organic solvent exposure and hearing loss in a cohort of aluminium workers.

OBJECTIVES: Organic solvent exposure has been shown to cause hearing loss in animals and humans. Less is known about the risk of hearing loss due to solvent exposures typically found in US industry. The authors performed a retrospective cohort study to examine the relationship between solvent exposure and hearing loss in US aluminium industry workers. METHODS: A cohort of 1319 workers aged 35 years or less at inception was followed for 5 years. Linkage of employment, industrial hygiene and audiometric surveillance records allowed for estimation of noise and solvent exposures and hearing loss rates over the study period. Study subjects were classified as "solvent exposed" or not, on the basis of industrial hygiene records linked with individual job histories. High frequency hearing loss was modelled as both a continuous and a dichotomous outcome. RESULTS: Typical solvent exposures involved mixtures of xylene, toluene and/or methyl ethyl ketone (MEK). Recorded solvent exposure levels varied widely both within and between jobs. In a multivariate logistic model, risk factors for high frequency hearing loss included age (OR = 1.06, p = 0.004), hunting or shooting (OR = 1.35, p = 0.049), noisy hobbies (OR = 1.74, p = 0.01), baseline hearing level (OR = 1.04, p<0.001) and solvent exposure (OR = 1.87, p = 0.004). A multivariate linear regression analysis similarly found significant associations between high frequency hearing loss and age (p<0.001), hunting or shooting (p<0.001), noisy hobbies (p = 0.03), solvent exposure (p<0.001) and baseline hearing (p = 0.03). CONCLUSION: These results suggest that occupational exposure to organic solvent mixtures is a risk factor for high frequency hearing loss, although the data do not allow conclusions about dose-response relationships. Industries with solvent-exposed workers should include such workers in hearing conservation programs.

Potential ototoxicity of aluminum in hemodialysis patients.

OBJECTIVES/HYPOTHESIS: Aluminum (Al) is a neurotoxin in both human and animal models. Al accumulation is usually observed in patients with end-stage renal disease (ESRD). To clarify whether Al also exhibits toxic effects on the specified neural organ of inner ear, we recruited hemodialysis (HD) patients to investigate the effect of serum Al level on the auditory physiology. STUDY DESIGN: Forty patients in maintenance HD as well as 40 age-matched healthy subjects without hearing complaints were enrolled. The auditory function tests, including pure-tone audiometry (PTA), distortion-product otoacoustic emissions (DPOAEs), and auditory brainstem response (ABR) were performed in all subjects. The serum Al levels determined within 3 months of auditory tests were used for analysis. RESULTS: High-frequency hearing impairment was the predominant auditory dysfunction in HD patients who showed worse high-tone hearing level on PTA and diminished amplitudes of DPOAEs at 3 K and 4 K as compared with the controls (P < .001). Age was a significant factor determining the auditory dysfunction in both HD patients and control subjects. After age correction, serum Al level correlated reversely with the amplitude of DPOAEs-2 K (P = .002), but not with amplitudes of DPOAEs-3 K, -4 K, hearing levels on PTA, or wave latencies on ABR. CONCLUSION: High-frequency hearing impairment is a common presentation in HD patients. Serum Al level correlates reversely with the amplitude of DPOAEs-2 K but not those of DPOAEs-3 K, -4 K, hearing levels on PTA, and wave latencies on ABR. Possibly, the correlation between the Al level and the high-frequency OAE results was obscured by the significantly diminished amplitudes of DPOAEs-3 K, -4 K in ESRD patients. These results implicate that the effect of Al is mainly of cochlear origin rather than of retrocochlear origin.

Distortion product otoacoustic emissions: an objective technique for the screening of hearing loss in children treated with platin derivatives.

In order to develop a sensitive audiometric protocol for identifying ototoxicity in children, a retrospective study of 16 children treated with cisplatin and/or carboplatin was performed. Audiometric testing was done by means of pure-tone threshold audiometry (PTA), high-frequency audiometry (HFA), and distortion product otoacoustic emissions (DPOAEs). Cisplatin caused a sensorineural high-frequency hearing loss in the study group compared to the controls (p < 0.01). Sixty-six percent of the cisplatin patients had a grade 2 or 3 ototoxicity. However, ototoxicity was not found in the patients treated with carboplatin. An excellent correlation was found between DPOAE levels and results obtained by audiometry (r = 0.82). Patients exposed to cisplatin are at significant risk for the development of drug-induced sensorineural hearing loss. Because of the several advantages of DPOAEs (noninvasive, objective, rapid, easy to use, sensitive) this method should be added in the audiological follow-up in infants and toddlers.

Relationship between cisplatin administration and the development of ototoxicity.

PURPOSE: To determine the auditory toxicity associated with dose- and schedule- intensive cisplatin/gemcitabine chemotherapy in non-small-cell lung carcinoma patients. PATIENTS AND METHODS: Patients were treated with gemcitabine followed by cisplatin according to an interpatient dose-escalation scheme. Patients were randomly assigned to receive treatment once a week for 6 weeks or once every 2 weeks for 4 weeks. The following cohorts of patients were treated with a reversed schedule once every 2 weeks, in which cisplatin was followed by gemcitabine. The dose-intensity of cisplatin was equal in both schedules. Audiometric evaluations were obtained for each ear at several frequencies. Mean hearing loss after cisplatin treatment was computed for each dose level at each tested frequency in each ear at baseline and subsequent follow-up audiometry. Pure tone averages (PTAs) were also calculated. The pharmacokinetics of cisplatin was determined to study the correlation among the maximum drug concentration, the area under the curve of unbound platinum, and the development of ototoxicity. RESULTS: A total of 328 audiograms were analyzed. At the higher frequencies, a more severe hearing impairment was recorded. Most patients showed a decrease in hearing thresholds at dosages above 60 mg/m2 cisplatin at the higher frequencies. PTAs at 1, 2, and 4 kHz show a mean hearing loss of 19 dB after cisplatin administration at dosages above 90 mg/m2. Threshold shifts at 8 and 12.5 kHz after cisplatin administration were experienced at dosages above 60 mg/m2. CONCLUSION: Hearing loss after cisplatin therapy occurs mainly at high frequencies and at cisplatin dosages more than 60 mg/m2. It is more pronounced when cisplatin is given once every 2 weeks.