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1.  Prospective evaluation of cisplatin- and carboplatin-mediated ototoxicity in paediatric and adult soft tissue and osteosarcoma patients 
Oncology Letters  2012;5(1):311-315.
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.
PMCID: PMC3525486  PMID: 23255940
hearing; child; cancer; late effects; platinum compounds
2.  Ototoxicity in Children With High-Risk Neuroblastoma: Prevalence, Risk Factors, and Concordance of Grading Scales—A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2014;32(6):527-534.
Platinum-based therapy is the mainstay for management of high-risk neuroblastoma. Prevalence of platinum-related ototoxicity has ranged from 13% to 95% in previous reports; variability is attributable to small samples and disparate grading scales. There is no consensus regarding optimal ototoxicity grading. Furthermore, prevalence and predictors of hearing loss in a large uniformly treated high-risk neuroblastoma population are unknown. We address these gaps in our study.
Patients and Methods
Audiologic testing was completed after administration of cisplatin alone (< 400 mg/m2; exposure one) or after cisplatin (400 mg/m2) plus carboplatin (1,700 mg/m2; exposure two). Hearing loss was graded using four scales (American Speech-Language-Hearing Association; Brock; Chang; and Common Terminology Criteria for Adverse Events, version 3 [CTCAEv3]).
Of 489 eligible patients, 333 had evaluable audiologic data. Median age at diagnosis was 3.3 years. Prevalence of severe hearing loss differed by scale. For those in the exposure-one group, prevalence ranged from 8% per Brock to 47% per CTCAEv3 (Brock v CTCAEv3 and Chang, P < .01; CTCAEv3 v Chang, P = .16); for those in the exposure-two group, prevalence ranged from 30% per Brock to 71% per CTCAEv3 (all pair-wise comparisons, P < .01). In patients requiring hearing aids, hearing loss was graded as severe in 49% (Brock), 91% (Chang), and 100% (CTCAEv3). Risk factors for severe hearing loss included exposure to cisplatin and carboplatin compared with cisplatin alone and hospitalization for infection.
Severe hearing loss is prevalent among children with high-risk neuroblastoma. Exposure to cisplatin combined with myeloablative carboplatin significantly increases risk. The Brock scale underestimates severe hearing loss and should be used with caution in this setting.
PMCID: PMC3918536  PMID: 24419114
3.  Risk Factors for Cisplatin-Associated Ototoxicity in Pediatric Oncology Patients 
Pediatric blood & cancer  2012;59(1):144-148.
Cisplatin is an effective chemotherapy agent against several pediatric malignancies. One of its side effects is irreversible sensorineural hearing damage that is highly variable with a reported incidence of 22–70%. The aim of this study was to evaluate the incidence and identify clinical predictors of cisplatin-related ototoxicity.
We performed a retrospective chart review of 102 pediatric patients who had completed cisplatin therapy for osteosarcoma, neuroblastoma, hepatoblastoma, or germ cell tumor. Patients were diagnosed at Riley Hospital for Children between January 1995 and June 2008, were less than 18 years old at diagnosis, and had normal hearing prior to therapy. Audiograms were scored using the Brock scale (0–4), a validated grading system for cisplatin-related hearing loss.
Forty-two percent of the patients experienced hearing loss and 28% had moderate to severe ototoxicity (Brock score ≥2). Males were at significantly greater risk for developing hearing loss than were females (P = 0.005, OR 4.812). Age at cancer diagnosis was inversely related to severity of ototoxicity. Patients who suffered Brock grade 3 ototoxicity had a mean age of 4.5 years versus 11.5 years and 7.2 years for grades 1 and 2, respectively (P = 0.02). Cumulative cisplatin dose was also identified as a risk factor for development of ototoxicity (P = 0.03).
Gender and cumulative dose are important clinical biomarkers of cisplatin ototoxicity. Severity of ototoxicity may be inversely related to age at time of exposure, with very young patients exhibiting higher grades of hearing loss following cisplatin therapy.
PMCID: PMC3767972  PMID: 22431292
cisplatin; hearing loss; ototoxicity; risk factors
4.  Ototoxicity evaluation in medulloblastoma patients treated with involved field boost using intensity-modulated radiation therapy (IMRT): a retrospective review 
Ototoxicity is a known side effect of combined radiation therapy and cisplatin chemotherapy for the treatment of medulloblastoma. The delivery of an involved field boost by intensity modulated radiation therapy (IMRT) may reduce the dose to the inner ear when compared with conventional radiotherapy. The dose of cisplatin may also affect the risk of ototoxicity. A retrospective study was performed to evaluate the impact of involved field boost using IMRT and cisplatin dose on the rate of ototoxicity.
Data from 41 medulloblastoma patients treated with IMRT were collected. Overall and disease-free survival rates were calculated by Kaplan-Meier method Hearing function was graded according to toxicity criteria of Pediatric Oncology Group (POG). Doses to inner ear and total cisplatin dose were correlated with hearing function by univariate and multivariate data analysis.
After a mean follow-up of 44 months (range: 14 to 72 months), 37 patients remained alive, with two recurrences, both in spine with CSF involvement, resulting in a disease free-survival and overall survival of 85.2% and 90.2%, respectively.
Seven patients (17%) experienced POG Grade 3 or 4 toxicity. Cisplatin dose was a significant factor for hearing loss in univariate analysis (p < 0.03). In multivariate analysis, median dose to inner ear was significantly associated with hearing loss (p < 0.01). POG grade 3 and 4 toxicity were uncommon with median doses to the inner ear bellow 42 Gy (p < 0.05) and total cisplatin dose of less than 375 mg/m2 (p < 0.01).
IMRT leads to a low rate of severe ototoxicity. Median radiation dose to auditory apparatus should be kept below 42 Gy. Cisplatin doses should not exceed 375 mg/m2.
PMCID: PMC4118158  PMID: 25041714
Medulloblastoma; Hearing loss; Intensity-modulated radiotherapy; Cisplatin; Quality of life
5.  Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale 
Journal of Clinical Oncology  2012;30(19):2408-2417.
The platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important.
Patients and Methods
This review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection.
Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally involves antioxidant thiol agents. Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects. Route of administration and optimal timing relative to platinum therapy are critical issues. In addition, international standards for grading and comparing ototoxicity are essential to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss.
Collaborative prospective basic and clinical trial research is needed to reduce the incidence of irreversible platinum-induced hearing loss, and optimize cancer control. Wide use of the new internationally agreed-on SIOP Boston ototoxicity scale in current and future otoprotection trials should help facilitate this goal.
PMCID: PMC3675696  PMID: 22547603
6.  Auditory Complications in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Studya 
Pediatric blood & cancer  2011;57(1):126-134.
Studies have found associations between cancer therapies and auditory complications, but data are limited on long-term outcomes and risks associated with multiple exposures.
The Childhood Cancer Survivor Study is a retrospective cohort investigating health outcomes of long-term survivors (5+ years) diagnosed and treated between 1970 and 1986 compared to a randomly selected sibling cohort. Questionnaires were completed by 14,358 survivors of childhood cancer and 4,023 sibling controls. Analysis determined the first occurrence of four auditory conditions in two time periods: diagnosis to ≥ 5 years post diagnosis, and > 5 years post diagnosis. Multivariable analyses determined the relative risks (RR) and 95% confidence interval (CI) of auditory conditions by treatment exposure.
Five or more years from cancer diagnosis, survivors were at increased risk of problems hearing sounds (RR=2.3; 95% CI: 1.8–2.8), tinnitus (RR=1.7; 95% CI: 1.4–2.1), hearing loss requiring an aid (RR=4.4; 95% CI: 2.8–6.9), and hearing loss in 1 or both ears not corrected by a hearing aid (RR=5.2; 95% CI: 2.8–9.5), when compared to siblings. Temporal lobe and posterior fossa radiation was associated with these outcomes in a dose-dependent fashion. Exposure to platinum compounds was associated with an increased risk of problems hearing sounds (RR=2.1; 95% CI: 1.3–3.2), tinnitus (RR=2.8; 95% CI: 1.9–4.2), and hearing loss requiring an aid (RR=4.1; 95% CI:2.5–6.7)
Childhood cancer survivors are at risk of developing auditory complications. Radiation and platinum compounds are determinants of this risk. Follow-up is needed to evaluate the impact of auditory conditions on quality of life.
PMCID: PMC3091978  PMID: 21328523
late effects of therapy; radiation therapy
7.  Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy 
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.
PMCID: PMC3123575  PMID: 21635776
Proton; radiotherapy; pediatric; medulloblastoma; ototoxicity
8.  Concordance between the Chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma 
Pediatric blood & cancer  2013;61(4):601-605.
Reporting ototoxicity is frequently complicated by use of various ototoxicity criteria. The International Society of Pediatric Oncology (SIOP) ototoxicity grading scale was recently proposed for standardized use in reporting hearing loss outcomes across institutions. The aim of this study was to evaluate the concordance between the Chang and SIOP ototoxicity grading scales. Differences between the two scales were identified and the implications these differences may have in the clinical setting were discussed.
Audiological evaluations were reviewed for 379 patients with newly diagnosed medulloblastoma (ages 3–21 years). Each patient was enrolled on one of two St. Jude clinical protocols that included craniospinal radiation therapy and four courses of 75 mg/m2 cisplatin chemotherapy. The latest audiogram conducted 5.5 – 24.5 months post-protocol treatment initiation was graded using the Chang and SIOP ototoxicity criteria. Clinically significant hearing loss was defined as Chang grade ≥ 2a and SIOP ≥2. Hearing loss was considered serious (requiring a hearing aid) at the level of Chang grade ≥ 2b and SIOP ≥ 3.
A strong concordance was observed between the Chang and SIOP ototoxicity scales (Stuart’s tau-c statistic = 0.89, 95% CI: 0.86, 0.91). Among those patients diagnosed with serious hearing loss, the two scales were in good agreement. However, the scales deviated from one another in classifying patients with less serious or no hearing loss.
Although discrepancies between the Chang and SIOP ototoxicity scales exist primarily for patients with no or minimal hearing loss, the scales share a strong concordance overall.
PMCID: PMC4371725  PMID: 24504791
ototoxicity; hearing loss; cisplatin; late effects; medulloblastoma
9.  Adult medulloblastoma: multiagent chemotherapy. 
Neuro-Oncology  2001;3(1):29-34.
In this study, the records of 17 adult patients with medulloblastoma treated with craniospinal radiation and 1 of 2 multiagent chemotherapy protocols were reviewed for progression-free survival, overall survival, and toxicity, and the patients were compared with each other and with similarly treated children and adults. Records of patients treated at 3 institutions were reviewed. Seventeen medulloblastoma patients (11 female, 6 male) with a median age of 23 years (range, 18-47 years) were treated with surgery, craniospinal radiation (CSRT) plus local boost, and 1 of 2 adjuvant chemotherapy regimens. All tumors were infratentorial (10 in 4th ventricle and 7 in left or right hemisphere). Ten patients presented with hydrocephalus, and 7 of them were shunted. Eight patients had gross total resection, 7 had subtotal resection (>50% removed), and 2 had partial resection (<50% removed). Postoperatively, 3 patients had positive cytology and 3 had positive spinal MRI. Five patients were classified as good risk and 12 were classified as poor risk (Chang staging system). Ten patients were treated with the "Packer protocol," consisting of CSRT plus weekly vincristine followed by 8 cycles of cisplatin, lomustine, and vincristine. Seven patients were treated with the Pediatric Oncology Group (POG) protocol, consisting of alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine, followed by CSRT. Eight of 17 patients relapsed, with all 8 relapsing at the primary site. Other relapse sites included the leptomeninges (5), bone (1), and brain (1). The estimated median relapse-free survival (Kaplan-Meier) for all patients was 48 months (95% confidence interval, >26 months to infinity). Median relapse-free survival for patients on the Packer protocol was 26 months, and for those on the POG regimen was 48 months (P = 0.410). Five of 10 on the Packer protocol were relapse-free, while 4 of 7 were relapse-free on the POG regimen. Two patients relapsed during chemotherapy and 6 relapsed after completing all therapy at 18, 18, 26, 30, 40, and 48 months. The estimated median survival of all patients was 56 months (95% confidence interval, 27 to infinity) with 11 patients alive; for the Packer protocol, median survival was 36 months, and for the POG protocol, it was 57 months (P = 0.058). The hazard ratio was 0 (95% confidence interval, 0 to infinity). Toxicity during the Packer protocol was moderately severe, with only 1 of 10 patients able to complete all therapy. Two patients had severe abdominal pain during CSRT + vincristine, and 5 had peripheral neuropathy during vincristine therapy. Hearing loss (>20 dB) occurred in 7, neutropenia (<500 microl) in 6, thrombocytopenia (<50,000 microl) in 6, nephrotoxicity (>25% decrease by creatinine clearance) in 2, and decreased pulmonary function (diffusing capacity for carbon monoxide decrease >40%) in 1. On the POG protocol, only 1 patient had persistent nausea and vomiting, 2 had peripheral neuropathy, and 3 had hearing deficit (>20 dB) or tinnitus. The POG and Packer protocols did not have a statistically significant difference in relapse-free or overall survival because of the small sample size. The POG protocol seemed to have less nonhematologic toxicity. Adults on the Packer protocol appeared to have shorter median survival and greater toxicity than did children. To know whether adding adjuvant chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.
PMCID: PMC1920599  PMID: 11305414
10.  Cisplatin and Cranial Irradiation-Related Hearing Loss in Children 
The Ochsner Journal  2012;12(3):191-196.
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.
PMCID: PMC3448239  PMID: 23049454
Cisplatin; cranial irradiation; ototoxicity; pediatric brain tumor
11.  The HEAR-QL: Quality of Life Questionnaire for Children with Hearing Loss 
Few quality of life (QOL) assessment tools are available for children with specific chronic conditions, and none have been designed specifically for children with hearing loss (HL). A validated hearing-related QOL questionnaire could help clinicians determine whether an intervention is beneficial and whether one intervention is better than another.
To examine QOL in children with HL and assess the validity, reliability, and factor structure of a new measure, the Hearing Environments and Reflection on Quality of Life (HEAR-QL) questionnaire.
Research Design
A descriptive and correlational study of a convenience sample of children.
Study Sample
Participants included 35 children with unilateral HL, 45 with bilateral HL, and 35 siblings with normal hearing.
Data Collection and Analysis
Children 7-12 years old were recruited by mail from a tertiary-care pediatric otolaryngology practice and the local county's Special School District. With parent consent, children completed the validated Pediatric Quality of Life Inventory™ (PedsQL™) 4.0 and a 35-item HEAR-QL questionnaire. The factor structure of the HEAR-QL was determined through principal components analysis (PCA), and mean scores were computed for each subscale and the total HEAR-QL. Three weeks following return of the initial questionnaires, a second HEAR-QL questionnaire was sent to participants to assess test-retest reliability. Both PedsQL and HEAR-QL scores were compared between children with and without HL, between children with unilateral and bilateral HL, and between children who used and did not use a hearing device using analysis of variance. Sensitivity and specificity were calculated for both the HEAR-QL and PedsQL. A multivariable, hierarchical linear regression analysis was conducted with independent variables associated with HEAR-QL in unadjusted tests.
Using exploratory PCA, the 35-item HEAR-QL was reduced to 26 items (Cronbach's α=0.97; sensitivity 91% and specificity 92% at cut-off score of 93.5) loading on 3 factors: difficulty hearing in certain environments/situations (Environments α=0.97), impact of HL on social/sports activities (Activities α=0.92), and impact of HL on child's feelings (Feelings α=0.88). Sensitivity 78.8% and specificity 30.9% at a cut-off score of 69.6 on the PedsQL ((at-risk for impaired QOL) were lower than for the HEAR-QL. Participants with HL reported significantly lower mean total HEAR-QL scores (71 [SD 18] versus 98 [SD 5]; p < 0.001), but not mean total PedsQL scores (77 [SD 14] versus 83 [SD 15]; p = 0.47), than participants with normal hearing. Among children with bilateral HL, children who used a hearing device reported lower mean total HEAR-QL scores (p = 0.01), but not mean total PedsQL scores (p = 0.55), than children who did not use a hearing device. The intraclass correlation (ICC) for test-retest reliability for the 26-item HEAR-QL total score was .83. Hearing status and use of a device were independently associated with the HEAR-QL, and the variables in the model accounted for 46% of the HEAR-QL total score variance.
The HEAR-QL appears to be a valid, reliable, and sensitive questionnaire for children with HL. The HEAR-QL was better able than the PedsQL to distinguish between children with and without HL and can help evaluate interventions for children with HL.
PMCID: PMC3273903  PMID: 22212764
Hearing loss; Children; Quality of life; Questionnaire
12.  Effects of Early Auditory Experience on the Spoken Language of Deaf Children at 3 Years of Age 
Ear and hearing  2006;27(3):286-298.
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.
PMCID: PMC2880472  PMID: 16672797
13.  Outcomes of Early- and Late-identified Children at 3 Years of Age: Findings from a Prospective Population-based Study 
Ear and hearing  2013;34(5):535-552.
To address the question of whether, on a population level, early detection and amplification improve outcomes of children with hearing impairment.
All families of children who were born between 2002 and 2007, and who presented for hearing services below 3 years of age at Australian Hearing pediatric centers in New South Wales, Victoria and Southern Queensland were invited to participate in a prospective study on outcomes. Children’s speech, language, functional and social outcomes were assessed at 3 years of age, using a battery of age-appropriate tests. Demographic information relating to the child, family, and educational intervention was solicited through the use of custom-designed questionnaires. Audiological data were collected from the national database of Australian Hearing and records held at educational intervention agencies for children. Regression analysis was used to investigate the effects of each of 15 predictor variables, including age of amplification, on outcomes.
Four hundred and fifty-one children enrolled in the study, 56% of whom received their first hearing-aid fitting before 6 months of age. Based on clinical records, 44 children (10%) were diagnosed with auditory neuropathy spectrum disorder. There were 107 children (24%) reported to have additional disabilities. At 3 years of age, 317 children (70%) were hearing-aid users and 134 children (30%) used cochlear implants. Based on parent reports, about 71% used an aural/oral mode of communication, and about 79% used English as the spoken language at home. Children’s performance scores on standardized tests administered at 3 years of age were used in a factor analysis to derive a global development factor score. On average, the global score of hearing-impaired children was more than one standard deviation (SD) below the mean of normal-hearing children at the same age. Regression analysis revealed that five factors, including female gender, absence of additional disabilities, less severe hearing loss, higher maternal education; and for children with cochlear implants, earlier age of switch-on; were associated with better outcomes at the 5% significance level. Whereas the effect of age of hearing aid fitting on child outcomes was weak, a younger age at cochlear implant switch-on was significantly associated with better outcomes for children with cochlear implants at 3 years of age.
Fifty-six percent of the 451 children were fitted with hearing aids before 6 months of age. At 3 years of age, 134 children used cochlear implants and the remaining children used hearing aids. On average, outcomes were well below population norms. Significant predictors of child outcomes include: presence/absence of additional disabilities, severity of hearing loss, gender, maternal education; together with age of switch-on for children with cochlear implants.
PMCID: PMC3681915  PMID: 23462376
outcomes; hearing-impaired children; language; predictors; cochlear implants; hearing aids; hearing loss; population study
14.  Carboplatin-Associated Ototoxicity in Children With Retinoblastoma 
Journal of Clinical Oncology  2012;30(10):1034-1041.
Carboplatin-induced ototoxicity remains poorly defined but is of potential great consequence in children with retinoblastoma. We retrospectively assessed the incidence of ototoxicity and its risk factors in children with retinoblastoma who were treated with carboplatin.
Patients and Methods
We reviewed the audiologic test results of 60 patients with retinoblastoma who received front-line treatment with systemic carboplatin and vincristine according to the St Jude RET-3 protocol (n = 23) or best clinical management (n = 37). Ototoxicity was evaluated by three different grading systems.
Twelve patients (20%) developed ototoxicity at some time after treatment initiation; however, ototoxicity resolved in two patients, and thus,10 patients (17%) had sustained hearing loss as documented at their most recent audiologic evaluation. Nine of these 10 patients had grade 3 or 4 ototoxicity, and nine patients were less than 6 months of age at the start of chemotherapy. Age at the start of chemotherapy was the only risk factor identified as a significant predictor of sustained hearing loss. Younger age was associated with an increased incidence of hearing loss. The different ototoxicity grading systems showed good overall agreement in the identification of patients with ototoxicity. Agreement was greatest between the Brock and Children's Cancer Group systems.
We found that young patients with retinoblastoma who were treated with systemic carboplatin had a higher incidence of ototoxicity than previously reported. Younger patients (< 6 months of age at the start of treatment) were more likely to have ototoxicity than were older patients. Children treated with carboplatin should routinely undergo thorough, long-term audiologic monitoring.
PMCID: PMC3341147  PMID: 22370329
15.  Longitudinal Development of Phonology and Morphology in Children with Late-Identified Mild-Moderate Sensorineural Hearing Loss 
Ear and hearing  2010;31(5):625-635.
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.
PMCID: PMC2932864  PMID: 20548239
16.  The Design and Screening of Drugs to Prevent Acquired Sensorineural Hearing Loss 
Expert opinion on drug discovery  2011;6(5):491-505.
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.
Areas covered
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.
Expert opinion
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.
PMCID: PMC3395201  PMID: 22646075
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
17.  Pediatric cochlear implantation: an update 
Deafness in pediatric age can adversely impact language acquisition as well as educational and social-emotional development. Once diagnosed, hearing loss should be rehabilitated early; the goal is to provide the child with maximum access to the acoustic features of speech within a listening range that is safe and comfortable. In presence of severe to profound deafness, benefit from auditory amplification cannot be enough to allow a proper language development. Cochlear implants are partially implantable electronic devices designed to provide profoundly deafened patients with hearing sensitivity within the speech range. Since their introduction more than 30 years ago, cochlear implants have improved their performance to the extent that are now considered to be standard of care in the treatment of children with severe to profound deafness. Over the years patient candidacy has been expanded and the criteria for implantation continue to evolve within the paediatric population. The minimum age for implantation has progressively reduced; it has been recognized that implantation at a very early age (12–18 months) provides children with the best outcomes, taking advantage of sensitive periods of auditory development. Bilateral implantation offers a better sound localization, as well as a superior ability to understand speech in noisy environments than unilateral cochlear implant. Deafened children with special clinical situations, including inner ear malformation, cochlear nerve deficiency, cochlear ossification, and additional disabilities can be successfully treated, even thogh they require an individualized candidacy evaluation and a complex post-implantation rehabilitation. Benefits from cochlear implantation include not only better abilities to hear and to develop speech and language skills, but also improved academic attainment, improved quality of life, and better employment status. Cochlear implants permit deaf people to hear, but they have a long way to go before their performance being comparable to that of the intact human ear; researchers are looking for more sophisticated speech processing strategies as well as a more efficient coupling between the electrodes and the cochlear nerve with the goal of dramatically improving the quality of sound of the next generation of implants.
PMCID: PMC4282008  PMID: 25179127
Sensorineural hearing loss; Cochlear implantation; Hearing rehabilitation; Surgery
18.  Symptoms of Psychopathology in Hearing-Impaired Children 
Ear and Hearing  2015;36(4):e190-e198.
Children with hearing loss are at risk of developing psychopathology, which has detrimental consequences for academic and psychosocial functioning later in life. Yet, the causes of the extensive variability in outcomes are not fully understood. Therefore, the authors wanted to objectify symptoms of psychopathology in children with cochlear implants or hearing aids, and in normally hearing peers, and to identify various risk and protective factors.
The large sample (mean age = 11.8 years) included three subgroups with comparable age, gender, socioeconomic status, and nonverbal intelligence: 57 with cochlear implants, 75 with conventional hearing aids, and 129 children who were normally hearing. Psychopathology was assessed by means of self- and parent-report measures.
Children with cochlear implants showed similar levels of symptoms of psychopathology when compared with their normally hearing peers, but children with hearing aids had significantly higher levels of psychopathological symptoms, while their hearing losses were approximately 43 dB lower than those of children with implants. Type of device was related with internalizing symptoms but not with externalizing symptoms. Furthermore, lower age and sufficient language and communication skills predicted less psychopathological symptoms.
Children who are deaf or profoundly hearing impaired and have cochlear implants have lower levels of psychopathological symptoms than children with moderate or severe hearing loss who have hearing aids. Most likely, it is not the type of hearing device but rather the intensity of the rehabilitation program that can account for this difference. This outcome has major consequences for the next generation of children with hearing loss because children with profound hearing impairment still have the potential to have levels of psychopathology that are comparable to children who are normally hearing.
Children with hearing loss are at risk for developing psychopathology, with detrimental consequences for academic and psychosocial functioning later in life. Yet the causes of the extensive variability in outcomes are not fully understood. This study showed that children who are deaf or profoundly hearing impaired and have cochlear implants have lower levels of psychopathological symptoms than children with moderate or severe hearing loss who have hearing aids. Most likely, it is not the type of hearing device, but rather the intensity of the rehabilitation program, that can account for this difference. Furthermore, lower age and sufficient language and communication skills predicted fewer psychopathological symptoms.
PMCID: PMC4478069  PMID: 25668391
Children; Cochlear implant; Hearing impairment; Mental health; Psychopathology
19.  Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study 
The Lancet Oncology  2013;14(9):834-842.
The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma.
SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1–A3: cisplatin 80 mg/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m2 per day in 24 h on days 1–3 and 22–24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m2 per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at, NCT00077389.
We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91–100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour lesions was achieved in 46 patients (74%). At the end of therapy, 49 (79%, 95% CI 67–88) of 62 patients were in complete remission. With a median follow-up of 52 months, 3-year event-free survival was 76% (95% CI 65–87) and 3-year overall survival was 83% (73–93). 60 (97%) patients had grade 3–4 haematological toxicity (anaemia, neutropenia, or thrombocytopenia) and 44 (71%) had at least one episode of febrile neutropenia. Other main grade 3 or 4 toxicities were documented infections (17 patients, 27%), anorexia (22, 35%), and mucositis (seven, 11%). One child died of fungal infection in neutropenia. Moderate-to-severe ototoxicity was documented in 31 (50%) patients. 18 serious adverse events (including two deaths) reflecting the observed side-effects were reported in the trial (the most common was ototoxicity in five patients).
The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma.
Cancer Research UK and Cancer Research Switzerland/Oncosuisse.
PMCID: PMC3730732  PMID: 23831416
20.  Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer. 
British Journal of Cancer  1998;77(8):1355-1362.
This study evaluates the degree and relevance of persisting ototoxicity after cisplatin-based standard-dose chemotherapy for testicular cancer, with emphasis on identification of potential factors for an increased risk of this late sequel. Hearing thresholds of 86 patients with a median age of 31 years (range 21-53 years) and a median follow-up time of 58 months (range 15-159 months) were assessed by conventional pure-tone audiometry. Interviews were conducted evaluating the patients' history with special regard to audiological risk factors, as well as circumstances of ototoxic symptoms. Details concerning treatment and patient variables were extracted retrospectively from the patients' charts. An additional screening programme assessed current body functions, blood parameters and other late toxicities. Symptomatic ototoxicity persisted in 20% of patients (59% tinnitus, 18% hearing loss, 23% both), while 10% had experienced completely reversible ototoxic symptoms for a duration of 1-18 months after treatment. Symptoms were bilateral in 81% of patients. Hearing thresholds were compatible with cisplatin-induced hearing loss in 42% of audiograms performed. Subjective (history) and objective (audiogram) findings were not always consistent. The following statistically significant risk factors for ototoxicity were established: high cumulative dose of cisplatin (P < 0.0001); history of noise exposure (P = 0.006). Additionally, high doses of vincristine (P = 0.001) seemed to result in reversible ototoxic symptoms. No other independent risk factors were identified. In conclusion, persisting ototoxicity represents a clinical sequel for approximately 20% of testicular cancer patients treated at standard dose but may affect more than 50% of patients receiving cumulative doses of cisplatin > 400 mg m(-2). Previous noise exposure may also result in a threefold increased risk for cisplatin ototoxicity. Future studies should use these risk factors as important stratification criteria for trials aiming at the evaluation and prevention of cisplatin-induced ototoxicity.
PMCID: PMC2150148  PMID: 9579846
21.  Glutathione S-Transferase P1 Single Nucleotide Polymorphism Predicts Permanent Ototoxicity in Children with Medulloblastoma 
Pediatric blood & cancer  2012;60(4):593-598.
Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy and clearing reactive oxygen species formed by radiation. We explored the relationship between the host GSTP1 105 A>G polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1 105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events.
The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children’s Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and logistic regression for toxicity comparisons.
Patients with a GSTP1 105 AG/GG genotype (vs. AA) or who had received high dose craniospinal radiation (≥ 34 Gy vs. <26 Gy) had a greater risk of requiring hearing aids than their counterparts (OR 4.0, 95%CI 1.2-13.6, and OR 3.1, 95%CI 1.1-8.8, respectively, n=69). Additionally, there was a statistically significant interaction between these variables. Compared with the lowest risk group (GSTP1 105 AA-low dose radiation), patients with a GSTP1 105 AG/GG genotype who received high dose radiation were 8.4 times more likely to require hearing aids (95%CI 1.4-49.9, p-trend=0.005, n=69). When adjusted for age, cumulative cisplatin dose, and amifostine use, the association remained.
The GSTP1 105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. Patients with this allele should be considered for clinical trials employing radiation dose modifications and cytoprotectant strategies.
PMCID: PMC3549321  PMID: 23065688
Glutathione S-Transferase; Polymorphism; Radiation; Ototoxicity; Medulloblastoma
22.  The effects of sign language on spoken language acquisition in children with hearing loss: a systematic review protocol 
Systematic Reviews  2013;2:108.
Permanent childhood hearing loss affects 1 to 3 per 1000 children and frequently disrupts typical spoken language acquisition. Early identification of hearing loss through universal newborn hearing screening and the use of new hearing technologies including cochlear implants make spoken language an option for most children. However, there is no consensus on what constitutes optimal interventions for children when spoken language is the desired outcome. Intervention and educational approaches ranging from oral language only to oral language combined with various forms of sign language have evolved. Parents are therefore faced with important decisions in the first months of their child’s life.
This article presents the protocol for a systematic review of the effects of using sign language in combination with oral language intervention on spoken language acquisition. Studies addressing early intervention will be selected in which therapy involving oral language intervention and any form of sign language or sign support is used. Comparison groups will include children in early oral language intervention programs without sign support. The primary outcomes of interest to be examined include all measures of auditory, vocabulary, language, speech production, and speech intelligibility skills. We will include randomized controlled trials, controlled clinical trials, and other quasi-experimental designs that include comparator groups as well as prospective and retrospective cohort studies. Case-control, cross-sectional, case series, and case studies will be excluded. Several electronic databases will be searched (for example, MEDLINE, EMBASE, CINAHL, PsycINFO) as well as grey literature and key websites. We anticipate that a narrative synthesis of the evidence will be required. We will carry out meta-analysis for outcomes if clinical similarity, quantity and quality permit quantitative pooling of data. We will conduct subgroup analyses if possible according to severity/type of hearing disorder, age of identification, and type of hearing technology.
This review will provide evidence on the effectiveness of using sign language in combination with oral language therapies for developing spoken language in children with hearing loss who are identified at a young age. The information from this review can provide guidance to parents and intervention specialists, inform policy decisions and provide directions for future research.
PROSPERO registration number
PMCID: PMC4029089  PMID: 24314335
Children; Hearing loss; Spoken language; Sign language; Outcomes; Systematic review
23.  Cerebrovascular disease in childhood cancer survivors 
Neurology  2009;73(22):1906-1913.
Curative therapy for childhood cancer has dramatically improved over past decades. Therapeutic radiation has been instrumental in this success. Unfortunately, irradiation is associated with untoward effects, including stroke and other cerebrovascular disease (CVD). The Children’s Oncology Group (COG) has developed guidelines for screening survivors at risk for persistent or late sequelae of cancer therapy.
This review summarizes the pathophysiology and relevant manifestations of radiation-induced CVD and outlines the specific patient groups at risk for early-onset stroke. The reader will be alerted to the availability of the COG recommendations for monitoring, and, when applicable, specific screening and treatment recommendations will be highlighted.
A multidisciplinary task force critically reviewed the existing literature and scored the evidence to establish the current COG guidelines for monitoring health of survivors treated with head and neck irradiation.
Previous head and neck exposure to therapeutic radiation is associated with latent CVD and increased risk for stroke in some patient groups. Common manifestations of radiation-induced CVD includes steno-occlusive disease, moyamoya, aneurysm, mineralizing microangiopathy, vascular malformations, and strokelike migraines.
Risk for stroke is increased in survivors of pediatric CNS tumors, Hodgkin lymphoma, and acute lymphoblastic leukemia who received radiation to the brain and/or neck. As the population of survivors ages, vigilance for stroke and cerebrovascular disease needs to continue based on specific exposures during curative cancer therapy.
= acute lymphoblastic leukemia;
= Childhood Cancer Survivor Study;
= confidence interval;
= Children’s Oncology Group;
= cerebrovascular disease;
= neurofibromatosis type I;
= radiation therapy.
PMCID: PMC2788797  PMID: 19812380
24.  Amifostine does not prevent platinum-induced hearing loss associated with the treatment of children with hepatoblastoma. A report of the Intergroup Hepatoblastoma Study P9645 as a part of the Children's Oncology Group 
Cancer  2009;115(24):5828-5835.
To determine if amifostine is effective in reducing the toxicities associated with the administration of platinum-containing regimens in children with hepatoblastoma (HB).
Patients were enrolled on P9645 beginning in March of 1999. Stage I/II patients received treatment with 4 cycles of cisplatin/5-fluorouracil/vincristine (C5V) +/− amifostine. Patients with Stage III/IV disease were randomized to receive treatment with six cycles of either C5V +/− amifostine or carboplatin alternating with cisplatin (CC) +/− amifostine. Patients randomized to receive amifostine were given a dose of 740 mg/m2 intravenously over 15 minutes prior to each administration of a platinum agent.
Eighty-two patients were considered in a special interim analysis of the incidence of toxicity. The disease outcome for patients receiving amifostine was similar to outcome in patients who did not receive amifostine (p = 0.22). The incidence of significant hearing loss (> 40 dB) was similar for patients treated with or without amifostine: 38% (14/37) vs. 38% (17/45) (p=0.68), respectively. There were no differences in the incidence of renal or bone marrow toxicities evaluated. Patients who received amifostine had a higher incidence of hypocalcemia (5% vs. 0.5%, p=0.00006).
Amifostine in the doses and schedule used in this study failed to significantly reduce the incidence of platinum-induced toxicities in patients with HB.
PMCID: PMC2795100  PMID: 19813275
Hepatoblastoma; Amifostine; Hearing; Ototoxicity
25.  Ototoxicity from Combined Cisplatin and Radiation Treatment: An In Vitro Study 
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.
PMCID: PMC2995915  PMID: 21151649

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