Platinum-compound chemotherapy is known to have ototoxic side-effects. However, there is a paucity of literature examining hearing function prospectively and longitudinally in cohorts containing paediatric and adult patients treated within the same cisplatin- or carboplatin-containing treatment trial protocols. In Germany, Austria and Switzerland, late effects of treatment for osteosarcoma and soft tissue sarcoma have been prospectively and longitudinally registered by the Late Effects Surveillance System since 1998. The aim of this study was to analyse cisplatin- and carboplatin-induced ototoxity in a group of 129 osteosarcoma and soft tissue sarcoma patients treated within the COSS-96, CWS-96 and CWS-2002P treatment trials. The cohort consisted of 112 children and 17 adults. The median age at diagnosis was 13.56 (IQR, 10.26–16.27) years. Follow-up was 6.97 (IQR, 0.87–15.63) months. Hearing function was examined by audiometry before and after platinum treatment. A total of 108 patients were treated with cisplatin with a median cumulative dose of 360 mg/m2. Thirteen patients received carboplatin with a median cumulative dose of 1500 mg/m2 and 8 patients were treated with both platinum compounds (median cisplatin dose, 240 mg/m2; IQR, 240–360 mg/m2 and median carboplatin dose: 1200 mg/m2; IQR, 600–3000 mg/m2). Following cessation of therapy, 47.3% of the patients demonstrated a hearing impairment, namely 55 children (49.1%) and 6 adults (42.1%). Out of thirteen children treated with carboplatin with a cumulative dose of 1500 mg/m2, six revealed a significant hearing impairment. Although ototoxicity caused by platinum compounds is considered irreversible, we identified hearing improvements over time in 11 children (9.8%) and 3 adults (17.6%). None of these patients received irradiation to the head. We conclude that hearing loss is frequent in children treated with protocols containing platinum compounds and recommend prospective testing via audiometry.
hearing; child; cancer; late effects; platinum compounds
Sensorineural hearing loss affects a high percentage of the population. Ototoxicity is a serious and pervasive problem in patients treated with cisplatin. Strategies to ameliorate ototoxicity without compromising on antitumor activity of treatments are urgently needed. Similar problems occur with aminoglycoside antibiotic therapy for infections. Noise-induced hearing loss affects a large number of people. The use of ear protection is not always possible or effective. The prevention of hearing loss with drug therapy would have a huge impact in reducing the number of persons with hearing loss from these major causes.
This review discusses significant research findings dealing with the use of protective agents against hearing loss caused by cisplatin, aminoglycoside antibiotics and noise trauma. The efficacy in animal studies and the application of these protective agents in clinical trials that are ongoing are presented.
The reader will gain new insights into current and projected future strategies to prevent sensorineural hearing loss from cisplatin chemotherapy, aminoglycoside antibiotic therapy and noise exposure. The future appears to offer numerous agents to prevent hearing loss caused by cisplatin, aminoglycoside antibiotics and noise. Novel delivery systems will provide ways to guide these protective agents to the desired target areas in the inner ear and will circumvent problems with therapeutic interference of anti-tumor and antibiotics agents and will minimize undesired side effects.
aminoglycoside antibiotics; anti-inflammatory agents; antioxidants; cisplatin; cochlea; drug delivery; nanotechnology; noise-induced hearing loss; ototoxicity; reactive oxygen species; sensorineural hearing loss; siRNA; stem cell therapy
Report a case of loss of cochlear implant benefit following cisplatin therapy to treat osteosarcoma. Examine the implications for the loci of cisplatin-associated cochleotoxicity.
Retrospective Case Review
Tertiary Referral Center
Single Case Study
Main Outcome Measure(s)
Cochlear implant programming levels
Increase in cochlear implant programming T- and C-levels following cisplatin therapy.
Cisplatin therapy likely affects spiral ganglion cells. It appears that auditory cells other than outer hair cells in the organ of Corti are affected by cisplatin since the hearing sensitivity of this patient with non-functioning outer hair cells declined after receiving chemotherapy. Implications of these findings are discussed.
cisplatin; ototoxicity; cochlear implant; spiral ganglion cells
Background: High doses of cisplatin and cranial radiotherapy (CRT) have been reported to cause irreversible hearing loss. The objective of this study was to examine the influence of cranial irradiation on cisplatin-associated ototoxicity in children with pediatric malignancies.
Methods: Serial audiograms were obtained for 33 children, age <16 years, treated with cisplatin-based chemotherapy (90-120 mg/m2 per cycle) with or without CRT. Eligible patients included those with normal baseline audiometric evaluations and without significant exposure to other ototoxic drugs. We defined significant hearing loss as a hearing threshold ≥30 dB at 2,000-8,000 Hz frequencies.
Results: The median age of our study population was 4.9 years (range 6 weeks to 16 years), and the male to female ratio was 0.8:1. The study population consisted of 15 Caucasians, 17 African-Americans, and 1 Hispanic. Fourteen patients had brain tumors, and 19 had other solid tumors. Thirteen patients were exposed to CRT, and 20 were not. Bilateral hearing loss was observed in 24/33 (73%) patients, with severe/profound (≥70 dB) impairment in 10/33 (30%) of all patients. Young age (<5 years), CRT, and brain tumors were independent prognostic factors predicting hearing loss.
Conclusion: The study demonstrated a high incidence of hearing loss in children treated with cisplatin and CRT. Consequently, we recommend monitoring these children for the early detection of hearing loss.
Cisplatin; cranial irradiation; ototoxicity; pediatric brain tumor
Hearing loss is common following chemoradiotherapy for children with medulloblastoma. Compared to photons, proton radiotherapy reduces radiation dose to the cochlea for these patients. Here we examine whether this dosimetric advantage leads to a clinical benefit in audiometric outcomes.
From 2006-2009, 23 children treated with proton radiotherapy for medulloblastoma were enrolled on a prospective observational study, through which they underwent pre- and 1 year post-radiotherapy pure-tone audiometric testing. Ears with moderate to severe hearing loss prior to therapy were censored, leaving 35 ears in 19 patients available for analysis.
The predicted mean cochlear radiation dose was 30 60Co-Gy Equivalents (range 19-43), and the mean cumulative cisplatin dose was 303 mg/m2 (range 298-330). Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (P < 0.05). There was partial sparing of mean post-radiation hearing thresholds at low-to-midrange frequencies and, consequently, the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was favorable (5%). Ototoxicity did not correlate with predicted dose to the auditory apparatus for proton-treated patients, potentially reflecting a lower-limit threshold for radiation effect on the cochlea.
Rates of high-grade early post-radiation ototoxicity following proton radiotherapy for pediatric medulloblastoma are low. Preservation of hearing in the audible speech range, as observed here, may improve both quality of life and cognitive functioning for these patients.
Proton; radiotherapy; pediatric; medulloblastoma; ototoxicity
Cisplatin is a chemotherapeutic agent that is widely-used in the treatment of solid tumors. Ototoxicity is a common side effect of cisplatin therapy, and often leads to permanent hearing loss. The sensory organs of the avian ear are able to regenerate hair cells after aminoglycoside ototoxicity. This regenerative response is mediated by supporting cells, which serve as precursors to replacement hair cells. Given the antimitotic properties of cisplatin, we examined whether the avian ear was also capable of regeneration after cisplatin ototoxicity. Using cell and organ cultures of the chick cochlea and utricle, we found that cisplatin treatment caused apoptosis of both auditory and vestibular hair cells. Hair cell death in the cochlea occurred in a unique pattern, progressing from the low frequency (distal) region toward the high frequency (proximal) region. We also found that cisplatin caused a dose-dependent reduction in the proliferation of cultured supporting cells as well as increased apoptosis in those cells. As a result, we observed no recovery of hair cells after ototoxic injury caused by cisplatin. Finally, we explored the potential for nonmitotic hair cell recovery via activation of Notch pathway signaling. Treatment with the γ-secretase inhibitor DAPT failed to promote the direct transdifferentiation of supporting cells into hair cells in cisplatin-treated utricles. Taken together, our data show that cisplatin treatment causes maintained changes to inner ear supporting cells and severely impairs the ability of the avian ear to regenerate either via proliferation or by direct transdifferentiation.
utricle; cochlea; vestibular; cisplatinum; sensory epithelium; hearing; auditory
Objective. Combined cisplatin (CDDP) and radiotherapy is increasingly being used to treat advanced head and neck cancers. As both CDDP and radiation can cause hearing loss, it is important to have a better understanding of the cellular and molecular ototoxic mechanisms involved in combined therapy. Procedure.
The effects of CDDP, radiation, and combined CDDP-radiation on the OC-k3 cochlear cell line were studied using MTS assay, flow cytometry, Western blotting, and microarray analysis. Results. Compared to using CDDP or radiation alone, its combined use resulted in enhanced apoptotic cell death and apoptotic-related gene expression, including that of FAS. Phosphorylation of p53 at Ser15 (a marker for p53 pathway activation in response to DNA damage) was observed after treatment with either CDDP or radiation. However, posttreatment activation of p53 occurred earlier in radiation than in CDDP which corresponded to the timings of MDM2 and TP53INP1 expression. Conclusion. Enhanced apoptotic-related gene expressions leading to increased apoptotic cell deaths could explain the synergistic ototoxicity seen clinically in combined CDDP-radiation therapy. CDDP and radiation led to differential temporal activation of p53 which suggests that their activation is the result of different upstream processes. These have implications in future antiapoptotic treatments for ototoxicity.
Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition.
To model the onset of drug resistance, and investigate DNA methylation and gene expression alterations associated with platinum resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation and mRNA expression microarray analyses. To identify chemoresistance-associated, biological pathways likely impacted by DNA methylation, promoter CGI methylation and mRNA expression profiles were integrated and subjected to pathway enrichment analysis.
Promoter CGI methylation revealed a positive association (Spearman correlation of 0.99) between the total number of hypermethylated CGIs and GI50 values (i.e., increased drug resistance) following successive cisplatin treatment cycles. In accord with that result, chemoresistance was reversible by DNA methylation inhibitors. Pathway enrichment analysis revealed hypermethylation-mediated repression of cell adhesion and tight junction pathways and hypomethylation-mediated activation of the cell growth-promoting pathways PI3K/Akt, TGF-beta, and cell cycle progression, which may contribute to the onset of chemoresistance in ovarian cancer cells.
Selective epigenetic disruption of distinct biological pathways was observed during development of platinum resistance in ovarian cancer. Integrated analysis of DNA methylation and gene expression may allow for the identification of new therapeutic targets and/or biomarkers prognostic of disease response. Finally, our results suggest that epigenetic therapies may facilitate the prevention or reversal of transcriptional repression responsible for chemoresistance and the restoration of sensitivity to platinum-based chemotherapeutics.
The drugs based on platinum metals represent one of the oldest, but also one of the most effective groups of chemotherapeutic agents. Thanks to many clinical studies it is known that resistance of tumor cells to drugs is a frequent cause of chemotherapy failure. With regard to platinum based drugs, multidrug resistance can also be connected with increased expression of low-molecular weight protein metallothionein (MT). This study aimed at investigating the interactions of MT with cisplatin or carboplatin, using the adsorptive transfer technique coupled with differential pulse voltammetry Brdicka reaction (AdTS DPV Brdicka reaction), and a comparison of in vitro results with results obtained in vivo. The results obtained from the in vitro study show a strong affinity between platinum based drugs and MT. Further, we analyzed extracts of neuroblastoma cell lines treated with cisplatin or carboplatin. It is clear that neuroblastoma UKF-NB-4 cisplatin-resistant and cisplatin-sensitive cell lines unlikely respond to the presence of the platinum-based cytostatics cisplatin and carboplatin. Finally, we determined the level of MT in samples from rabbits treated with carboplatin and patients with retinoblastoma treated with the same drug.
tumor disease; metallothionein; platinum based anticancer drugs; anticancer therapy; resistance; retinoblastoma
Morphological studies on presbycusis, or age-related hearing loss, have been performed in several different strains of mice that demonstrate hearing loss with auditory pathology. The C57BL/6 (C57) mouse is a known model of early onset presbycusis, while the CBA mouse is characterized by relatively late onset hearing loss. We performed this study to further understand how early onset hearing loss is related with the aging process of the cochlea.
We compared C57 cochlear pathology and its accompanying apoptotic processes to those in CBA mice. Hearing thresholds and outer hair cell functions have been evaluated by auditory brainstem response (ABR) recordings and distortion product otoacoustic emission (DPOAE).
ABR recordings and DPOAE studies demonstrated high frequency hearing loss in C57 mice at P3mo of age. Cochlear morphologic studies of P1mo C57 and CBA mice did not show differences in the organ of Corti, spiral ganglion, or stria vascularis. However, from P3mo and onwards, a predominant early outer hair cell degeneration at the basal turn of the cochlea in C57 mice without definitive degeneration of spiral ganglion cells and stria vascularis/spiral ligament, compared with CBA mice, was observed. Additionally, apoptotic processes in the C57 mice also demonstrated an earlier progression.
These data suggest that the C57 mouse could be an excellent animal model for early onset 'sensory' presbycusis in their young age until P6mo. Further studies to investigate the intrinsic or extrinsic etiologic factors that lead to the early degeneration of organ of Corti, especially in the high frequency region, in C57 mice may provide a possible pathological mechanism of early onset hearing loss.
Cochlea; Morphology; Hearing; Aging; Apoptosis
The objective of this study was to evaluate the efficacy and safety of pemetrexed plus cisplatin/carboplatin in locally advanced or metastatic non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy.
Fifty-three locally advanced or metastatic non-small cell lung cancer patients previously treated with platinum-based chemotherapy received pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin area under the curve (AUC) 5 every 21 days, with dexamethasone, folic acid and vitamin B12 being administered.
Median age was 52 years. Eastern Cooperative Oncology Group (ECOG) performance status was 0-2. Thirty-eight patients had stage IV tumors. Thirty-seven patients had adenocarcinoma (including 6 alveolar carcinoma patients), and fourteen patients had squamous cell carcinoma. Thirty-four patients were treated in second line, 15 in third line, and 4 in fourth line. Seven patients (13.2%) showed partial response; Thirty-six (67.9%) had stable disease. The median progression free survival time was 6.0 months and the median overall survival time was 10.0 months. The 1-year survival rate was 40.9%. Five (9.4%) and four (7.5%) patients experienced grade 3 or 4 leukopenia and thrombocytopenia, respectively. Nonhematological toxicities included grade 3 nausea/vomiting in 1 patient (1.9%), grade 3 rash in 1 patient, grade 4 diarrhea in 1 patient (1.9%) and grade 4 creatinine increase in 1 patient (1.9%).
Locally advanced or metastatic NSCLC patients previously treated with platinum-based chemotherapy could benefit from pemetrexed plus cisplatin/carboplatin chemotherapy with tolerable adverse events.
The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell lung cancer that cannot be treated with radiotherapy and in those with metastatic non-small-cell lung cancer and good performance status. This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with non-resectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or vinorelbine in patients with advanced and/or refractory solid tumours.
British Journal of Cancer (2002) 87, 825–833. doi:10.1038/sj.bjc.6600540 www.bjcancer.com
© 2002 Cancer Research UK
cisplatin; carboplatin; ZD0473; BBR3464; oxaliplatin; non-small-cell lung cancer
Cisplatin causes auditory impairment due to the apoptosis of auditory hair cells. There is no strategy to regulate ototoxicity by cisplatin thus far. Dansam-Eum (DSE) has been used for treating the central nerve system injury including hearing loss in Korea. However, disease-related scientific investigation by DSE has not been elucidated. Here, we demonstrated that DSE and its component rosmarinic acid (RA) were shown to inhibit apoptosis of the primary organ of Corti explants as well as the auditory cells. Administration of DSE and RA reduced the thresholds of the auditory brainstem response in cisplatin-injected mice. A molecular docking simulation and a kinetic assay show that RA controls the activity of caspase-1 by interaction with the active site of caspase-1. Pretreatment of RA inhibited caspase-1 downstream signal pathway, such as the activation of caspase-3 and 9, release of cytochrome c, translocation of apoptosis-inducing factor, up-regulation of Bax, down-regulation of Bcl-2, generation of reactive oxygen species, and activation of nuclear factor-κB. Anticancer activity by cisplatin was not affected by treatment with RA in SNU668, A549, HCT116, and HeLa cells but not B16F10 cells. These findings show that blocking a critical step by RA in apoptosis may be useful strategy to prevent harmful side effects of ototoxicity in patients with having to undergo chemotherapy.
Carboplatin, a platinum-containing anti-cancer drug used to treat a variety of cancers, induces ototoxicity. Since, reactive oxygen species (ROS) and nitric oxide (NO) seem to be responsible for this toxicity, the antioxidant, N-acetyl-L-cysteine (L-NAC), and NO synthetase inhibitor, N-nitro-L-arginine methyl ester (L-NAME) were predicted to have protective effects against carboplatin ototoxicity. The aim of this study was to test for the protective effects of L-NAC and L-NAME on cochlear hair cells and spiral ganglion neurons (SGNs).
Cochlear organotypic cultures and dissociated spiral ganglion neuron cultures, from mice postnatal day 5 cultures were used in this study. The cultures were treated with carboplatin alone or in combination with L-NAC or L-NAME, and carboplatin-induced damage was monitored.
Treatment with carboplatin induced a significant loss of outer hair cells, while inner hair cells were preserved in the cochlear organotypic cultures. Addition of L-NAC or L-NAME reduced the amount of carboplatin-induced hair cell damage; the differences did not reach statistical significance. However, carboplatin significantly decreased the number of surviving SGNs in dissociated cultures. The toxic effects were significantly reduced by addition of L-NAC or L-NAME. In addition, carboplatin induced the loss of neurites from the SGN somata, and this was not blocked with L-NAC or L-NAME.
The results of this study suggest that ROS and NO are involved in carboplatin-induced damage to hair cells and SGNs, and administration of L-NAC/L-NAME can be used to attenuate the toxicity.
Ototoxicity; Carboplatin; Nitric oxide; Spiral ganglion neuron; Inner hair cell; Outer hair cell; Mouse
Cisplatin is widely used for treating various solid tumors. However, this drug produces dose-limiting ototoxicity and nephrotoxicity, which significantly reduce the quality of life of cancer patients. While nephrotoxicity could be alleviated by diuresis, there is currently no approved treatment for hearing loss. Previous studies show that the ROS and inflammation are major contributors to cisplatin-induced hearing loss. In this study, we show that ROS trigger the inflammatory process in the cochlea by activating signal transducer and activator of transcription-1 (STAT1). Activation of STAT1 activation was dependent on ROS generation through NOX3 NADPH oxidase, knockdown of which by siRNA reduced STAT1 activation. Moreover, STAT1 siRNA protected against activation of p53, reduced apoptosis, reduced damage to OHCs and preserved hearing in rats. STAT1 siRNA attenuated the increase in inflammatory mediators, such as TNF-α, inhibition of which protected cells from cisplatin-mediated apoptosis. Finally, we showed that trans-tympanic administration of etanercept, a TNF-α antagonist, protected against OHC damage and cisplatin-induced hearing loss. These studies suggest that controlling inflammation by inhibition of STAT1-dependent pathways in the cochlea could serve as an effective approach to treat cisplatin ototoxicity and improve the overall quality of life for cancer patients.
cisplatin; hearing loss; STAT1; cochlea; inflammation; apoptosis
High-intensity and/or prolonged exposure to noise causes temporary or permanent threshold shifts in auditory perception. Occupational exposure to solvents or administration of clinically important drugs, such as aminoglycoside antibiotics and cisplatin, also can induce permanent hearing loss. The mechanisms by which these ototoxic insults cause auditory dysfunction are still being unraveled, yet they share common sequelae, particularly generation of reactive oxygen species, that ultimately lead to hearing loss and deafness. Individuals are frequently exposed to ototoxic chemical contaminants (e.g., fuel) and noise simultaneously in a variety of work and recreational environments. Does simultaneous exposure to chemical ototoxins and noise potentiate auditory dysfunction? Exposure to solvent vapor in noisy environments potentiates the permanent threshold shifts induced by noise alone. Moderate noise levels potentiate both aminoglycoside- and cisplatin-induced ototoxicity in both rate of onset and in severity of auditory dysfunction. Thus, simultaneous exposure to chemical ototoxins and moderate levels of noise can potentiate auditory dysfunction. Preventing the ototoxic synergy of noise and chemical ototoxins requires removing exposure to ototoxins and/or attenuating noise exposure levels when chemical ototoxins are present.
Noise; ototoxins; ototoxic drugs; synergistic effects; deafness
The contribution of parental suspicion in the original identification of a 16 year cohort of 171 children with varying degrees of hearing impairment who were screened and identified in childhood was studied. Only a quarter of the children with permanent hearing loss were identified as a result of parental concern. The presence of parental suspicion preceding the audiological diagnosis was also measured. Of the children with severe or profound deafness, the parents only suspected the presence of hearing loss in 44%. Parental suspicion was even lower for those with a mild or moderate permanent hearing loss, and for those with an otherwise symptomless conductive hearing loss caused by otitis media with effusion. Some parents did identify hearing impairment in their children, and parental suspicion should never be professionally disregarded. Most parents, however, experienced initial difficulty in recognising their children's hearing loss, even when the children were comparatively old. The study confirms the need to continue to identify deafness early by both parental vigilance and sensitive hearing screening programmes.
Subjective tinnitus is the perception of sound in the absence of an external source. Tinnitus is often accompanied by hearing loss but not everyone with hearing loss experiences tinnitus. We examined neuroanatomical alterations associated with hearing loss and tinnitus in three groups of subjects: those with hearing loss with tinnitus, those with hearing loss without tinnitus and normal hearing controls without tinnitus. To examine changes in gray matter we used structural MRI scans and voxel-based morphometry (VBM) and to identify changes in white matter tract orientation we used diffusion tensor imaging (DTI). A major finding of our study was that there were both gray and white matter changes in the vicinity of the auditory cortex for subjects with hearing loss alone relative to those with tinnitus and those with normal hearing. We did not find significant changes in gray or white matter in subjects with tinnitus and hearing loss compared to normal hearing controls. VBM analysis revealed that individuals with hearing loss without tinnitus had gray matter decreases in anterior cingulate and superior and medial frontal gyri relative to those with hearing loss and tinnitus. Region-of-interest analysis revealed additional decreases in superior temporal gyrus for the hearing loss group compared to the tinnitus group. Investigating effects of hearing loss alone, we found gray matter decreases in superior and medial frontal gyri in participants with hearing loss compared to normal hearing controls. DTI analysis showed decreases in fractional anisotropy values in the right superior and inferior longitudinal fasciculi, corticospnial tract, inferior fronto-occipital tract, superior occipital fasciculus, and anterior thalamic radiation for the hearing loss group relative to normal hearing controls. In attempting to dissociate the effect of tinnitus from hearing loss, we observed that hearing loss rather than tinnitus had the greatest influence on gray and white matter alterations.
Voxel-based morphometry; VBM; Diffusion Tensor Imaging; DTI; MRI; brain; structure; tinnitus; hearing loss; hearing impairment; gray matter; grey matter; white matter
By age three, typically developing children have achieved extensive vocabulary and syntax skills that facilitate both cognitive and social development. Substantial delays in spoken language acquisition have been documented for children with severe-profound deafness, even those with auditory oral training and early hearing aid use. This study documents the spoken language skills achieved by orally educated three-year-olds whose profound hearing loss was identified and hearing aids fitted between 1 and 30 months of age and who received a cochlear implant between 12 and 38 months of age. The purpose of the analysis was to examine the effects of age, duration and type of early auditory experience on spoken language competence at age 3.5.
The spoken language skills of 76 children who had used a cochlear implant for at least 7 months were evaluated via standardized 30-minute language sample analysis, a parent-completed vocabulary checklist, and a teacher language-rating scale. The children were recruited from and enrolled in oral education programs or therapy practices across the United States. Inclusion criteria included: presumed deaf since birth, English the primary language of the home, no other known conditions that interfere with speech/language development, enrolled in programs using oral education methods, and no known problems with the cochlear implant lasting over 30 days.
Strong correlations were obtained among all language measures. Therefore, principal components analysis was used to derive a single Language Factor score for each child. A number of possible predictors of language outcome were examined, including age at identification and intervention with a hearing aid, duration of use of a hearing aid, pre-implant PTA threshold with a hearing aid, PTA threshold with a cochlear implant, and duration of use of a cochlear implant/ age at implantation (the last two variables were practically identical since all children were tested between 40 and 44 months of age). Examination of the independent influence of these predictors through multiple regression analysis revealed that pre-implant aided PTA threshold and duration of CI use (i.e., age at implant) accounted for 58% of the variance in Language Factor scores. A significant negative coefficient associated with pre-implant aided threshold indicated that children with poorer hearing before implantation exhibited poorer language skills at age 3.5 years. Likewise, a strong positive coefficient associated with duration of implant use indicated that children who had used their implant for a longer period of time (i.e., who were implanted at an earlier age) exhibited better language at age 3.5 years. Age at identification and amplification was unrelated to language outcome, as was aided threshold with the cochlear implant. A significant quadratic trend in the relation between duration of implant use and language score revealed a steady increase in language skill (at age 3.5) for each additional month of use of a cochlear implant after the first 12 months of implant use. The advantage to language of longer implant use became more pronounced over time.
Longer use of a cochlear implant in infancy and very early childhood dramatically affects the amount of spoken language exhibited by three year old profoundly deaf children. In this sample, the amount of pre-implant intervention with a hearing aid was not related to language outcome at 3.5 years of age. Rather, it was cochlear implantation at a younger age that served to promote spoken language competence. The previously identified language-facilitating factors of early identification of hearing impairment and early educational intervention may not be sufficient for optimizing spoken language of profoundly deaf children unless it leads to early cochlear implantation.
The present work investigates developmental aspects of the duration of point vowels in children with normal hearing compared to those with hearing aids and cochlear implants at four and five years of age. Younger children produced longer vowels than older children, and children with hearing loss produced longer and more variable vowels than their normal hearing peers. In the current study, children with hearing aids and cochlear implants did not perform differently from each other. Test age and hearing loss did not interact, indicating parallel but delayed development in children with hearing loss compared with their typically-developing peers. Variability was found to be concentrated among the high vowels /u, i/ but not in the low vowels /æ, /. The broad findings of the present work are consistent with previous reports and contribute a detailed description of point vowel duration not in the literature.
linguistic timing; phonetic development; speech production; hearing aids; cochlear implants; childhood hearing disorders
Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II) (cisplatin)-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage). Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast) from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.
Studies of language development in children with mild-moderate hearing loss are relatively rare. Longitudinal studies of children with late-identified hearing loss have not been conducted, and they are relevant for determining how a period of unaided mild-moderate hearing loss impacts development. In recent years, newborn hearing screening programs have effectively reduced the ages of identification for most children with permanent hearing loss. However, some children continue to be identified late and research is needed to guide management decisions. Further, studies of this group may help to discern if language normalizes following intervention, and/or if certain aspects of language might be vulnerable to persistent delays. The current study examines the impact of late identification and reduced audibility on speech and language outcomes via a longitudinal study of four children with mild-moderate sensorineural hearing loss.
Longitudinal outcomes of four children with late-identified mild-moderate sensorinueral hearing loss were studied using standardized measures and language sampling procedures, from at or near the point of identification (28 – 41 months) through 84 months of age. The children with hearing loss were compared to ten age-matched children with normal hearing on a majority of the measures through 60 months of age. Spontaneous language samples were collected from mother-child interaction sessions, recorded at consistent intervals in a laboratory-based play setting. Transcripts were analyzed using computer-based procedures (Systematic Analysis of Language Transcripts) and the Index of Productive Syntax. Possible influences of audibility were explored by examining the onset and productive use of a set of verb tense markers, and by monitoring the children’s accuracy in use of morphological endings. Phonological samples at baseline were transcribed and analyzed using Computerized Profiling.
At entry to the study, the four children with hearing loss demonstrated language delays, with pronounced delays in phonological development. Three of the four children demonstrated rapid progress with development and interventions, and performed within the average range on standardized speech and language measures compared to age-matched children by 60-months of age. However, persistent differences from children with normal hearing were observed in the areas of morphosyntax, speech intelligibility in conversation, and production of fricatives. Children with mild-moderate hearing loss demonstrated later than typical emergence of certain verb tense markers, which may be related to reduced or inconsistent audibility.
The results of this study suggest that early communication delays will resolve for children with late-identified mild-moderate hearing loss, given appropriate amplification and intervention services. A positive result is that three of four children demonstrated normalization of broad language behaviors by 60-months of age, in spite of significant delays at baseline. However, these children are at risk for persistent delays in phonology at the conversational level and for accuracy in use of morphological markers. The ways in which reduced auditory experiences and audibility may contribute to these delays are explored, along with implications for evaluation of outcomes.
Cochlear implantees have improved speech production skills compared with those using hearing aids, as reflected in their acoustic measures. When compared to normal hearing controls, implanted children had fronted vowel space and their /s/ and /∫/ noise frequencies overlapped. Acoustic analysis of speech provides an objective index of perceived differences in speech production which can be precursory in planning therapy. The objective of this study was to compare acoustic characteristics of speech in cochlear implantees with those of normal hearing age matched peers to understand implications.
Group 1 consisted of 15 children with prelingual bilateral severe-profound hearing loss (age, 5-11 years; implanted between 4-10 years). Prior to an implant behind the ear, hearing aids were used; prior & post implantation subjects received at least 1 year of aural intervention. Group 2 consisted of 15 normal hearing age matched peers. Sustained productions of vowels and words with selected consonants were recorded. Using Praat software for acoustic analysis, digitized speech tokens were measured for F1, F2, and F3 of vowels; centre frequency (Hz) and energy concentration (dB) in burst; voice onset time (VOT in ms) for stops; centre frequency (Hz) of noise in /s/; rise time (ms) for affricates. A t-test was used to find significant differences between groups.
Significant differences were found in VOT for /b/, F1 and F2 of /e/, and F3 of /u/. No significant differences were found for centre frequency of burst, energy concentration for stops, centre frequency of noise in /s/, or rise time for affricates. These findings suggest that auditory feedback provided by cochlear implants enable subjects to monitor production of speech sounds.
Acoustic analysis of speech is an essential method for discerning characteristics which have or have not been improved by cochlear implantation and thus for planning intervention.
Acoustic analysis; Speech production; Cochlear implantees
Cisplatin ototoxicity affects different individuals in a widely variable manner. These variations are likely to be explained by genetic differences among those affected. It would be highly advantageous to identify genetic variants that predispose to cisplatin ototoxicity in order to minimize the risk to susceptible subgroups. Although this area of research is very important, only a few studies have rigorously examined the genetic basis for cisplatin-induced susceptibility to hearing loss. This article addresses recent progress in clarifying the incidence of cisplatin ototoxicity and the risk factors and controversies regarding the identifcation of genetic variants associated with cisplatin-induced hearing loss.
audiometry; cisplatin; COMT; genome-wide screening; glutathione; GST; GSTM1; GSTP1; megalin; ototoxicity; pharmacogenomics; SNP; TMPT; XPC
Inner ear hair cell loss is the most common pathology seen after ototoxic drug injury. While certain drugs such as aminoglycosides and cisplatin are well-known to have dramatic ototoxic effects, it is probable that there are other drugs that cause occult degrees of hair cell loss and lesser degrees of hearing loss. Anti-cancer drugs are particularly strong candidates due to their general cytotoxicity. We have screened a library of 88 anti-cancer drugs (National Cancer Institute Approved Oncology Drugs Set) for drugs that damage hair cells of the zebrafish lateral line. The screen identified four out of five known ototoxic drugs. The screen also identified four out of seven suspected ototoxic drugs (drugs that have isolated case reports of patients developing hearing loss after administration). Five additional drugs with no known ototoxicity were identified as potentially novel ototoxins. Additional dose–response curves were performed to evaluate relative toxicity. Since anti-cancer drugs are often used clinically in combination, we also performed dose–response curves for a variety of anti-cancer drug combinations and demonstrated synergistic toxicity in five out of ten drug combinations that we tested. These findings support the use of the zebrafish lateral line as a screening tool to detect ototoxic effects in drugs and also suggest that ototoxicity should be considered in terms of drug regimens rather than individual drugs.
zebrafish; hair cell death; anti-cancer drugs