Publications by authors named "Johnnie K Bass"

24 Publications

  • Page 1 of 1

Outcome and molecular analysis of young children with choroid plexus carcinoma treated with non-myeloablative therapy: results from the SJYC07 trial.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa168. Epub 2020 Dec 15.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Background: Choroid plexus carcinoma (CPC) is a rare and aggressive tumor of infancy without a clear treatment strategy. This study describes the outcomes of children with CPC treated on the multi-institutional phase 2 SJYC07 trial and reports on the significance of clinical and molecular characteristics.

Methods: Eligible children <3 years-old with CPC were postoperatively stratified to intermediate-risk (IR) stratum if disease was localized or high-risk (HR) stratum, if metastatic. All received high-dose methotrexate-containing induction chemotherapy. IR-stratum patients received focal irradiation as consolidation whereas HR-stratum patients received additional chemotherapy. Consolidation was followed by oral antiangiogenic maintenance regimen. Survival rates and potential prognostic factors were analyzed.

Results: Thirteen patients (median age: 1.41 years, range: 0.21-2.93) were enrolled; 5 IR, 8 HR. Gross-total resection or near-total resection was achieved in ten patients and subtotal resection in 3. Seven patients had -mutant tumors, including 4 who were germline carriers. Five patients experienced progression and died of disease; 8 (including 5 HR) are alive without progression. The 5-year progression-free survival (PFS) and overall survival rates were 61.5 ± 13.5% and 68.4 ± 13.1%. Patients with -wild-type tumors had a 5-year PFS of 100% as compared to 28.6 ± 17.1% for -mutant tumors ( = .012). Extent of resection, metastatic status, and use of radiation therapy were not significantly associated with survival.

Conclusions: Non-myeloablative high-dose methotrexate-containing therapy with maximal surgical resection resulted in long-term PFS in more than half of patients with CPC. mutational status was the only significant prognostic variable and should form the basis of risk-stratification in future trials.
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http://dx.doi.org/10.1093/noajnl/vdaa168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813199PMC
December 2020

Association of Hearing Impairment With Neurocognition in Survivors of Childhood Cancer.

JAMA Oncol 2020 09;6(9):1363-1371

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Importance: Despite advancements in cancer therapy and supportive care, childhood cancer survivors remain at risk for chronic morbidities associated with disease and treatment, such as hearing impairment (HI) and neurocognitive deficits. This study, to our knowledge, is the first to objectively measure hearing and neurocognitive function in a large cohort of long-term survivors of childhood cancer stratified by treatment exposures.

Objective: To assess the association of HI with neurocognitive function and the factors in HI that mediate neurocognitive outcomes in survivors of childhood cancer.

Design, Setting, And Participants: Data analyzed in this cross-sectional study were collected for the period April 25, 2007, to June 30, 2017, from participants in the St. Jude Lifetime Cohort Study (SJLIFE), an ongoing study that quantifies the long-term health outcomes of survivors of childhood cancer. Participants included those treated at St. Jude Children's Research Hospital (Memphis, Tennessee) for childhood cancer who survived 5 or more years after their original diagnosis and who were eligible for audiologic and neurocognitive testing. Hearing outcomes were coded using the Chang Ototoxicity Grading Scale. Data analysis was performed from March 22, 2019, to March 5, 2020.

Main Outcomes And Measures: Hearing and neurocognitive function. Survivors were grouped by hearing sensitivity (normal hearing [Chang grade 0], mild HI [Chang grades 1a, 1b, and 2a], or severe HI [Chang grade ≥2b]) and stratified by treatment exposure (platinum-only exposure group [treated with cisplatin and/or carboplatin chemotherapy], cochlear radiotherapy [RT] exposure group [treated with cochlear RT with or without platinum-based chemotherapy], or no exposure group [no platinum-based chemotherapy or cochlear RT]). Multivariable log-binomial models were adjusted for age at diagnosis, time since diagnosis, sex, and relevant treatment exposures.

Results: A total of 1520 survivors of childhood cancer were analyzed, among whom 814 were male survivors (53.6%), the median (interquartile range [IQR]) age was 29.4 (7.4-64.7) years, and the median (IQR) time since diagnosis was 20.4 (6.1-53.8) years. Prevalence and risk of severe HI among survivors were higher in survivors in the platinum-only (n = 107 [34.9%]; relative risk [RR], 1.68 [95% CI, 1.20-2.37]) or cochlear RT (n = 181 [38.3%]; RR, 2.69 [95% CI, 2.02-3.57) exposure group compared with those in the no exposure group (n = 65 [8.8%]). Severe HI was associated with deficits in verbal reasoning skills (no exposure group RR, 1.11 [95% CI, 0.50-2.43]; platinum-only exposure group RR, 1.93 [95% CI, 1.21-3.08]; cochlear RT exposure group RR, 2.00 [95% CI, 1.46-2.75]), verbal fluency (no exposure group RR, 1.86 [95% CI, 1.19-2.91]; platinum-only exposure group RR, 1.83 [95% CI, 1.24-2.71]; cochlear RT exposure group RR, 1.45 [95% CI, 1.09-1.94]), visuomotor speed (no exposure group RR, 1.87 [95% CI, 1.07-3.25]; platinum-only exposure group RR, 3.10 [95% CI, 1.92-4.99]; cochlear RT exposure group RR, 1.40 [95% CI, 1.11-1.78]), and mathematics skills (no exposure group RR, 1.90 [95% CI, 1.18-3.04]; platinum-only exposure group RR, 1.63 [95% CI, 1.05-2.53]; cochlear RT exposure group RR, 1.58 [95% CI, 1.15-2.18]), compared with survivors with normal hearing or with mild HI.

Conclusions And Relevance: Results of this study suggest that severe HI in childhood cancer survivors is associated with neurocognitive deficits independent of the neurotoxic treatment received. Early screening and intervention for HI may facilitate the development and maintenance of neurocognitive function and identify individuals at risk for impairment.
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http://dx.doi.org/10.1001/jamaoncol.2020.2822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393588PMC
September 2020

Spanish Pediatric Picture Identification Test.

Am J Audiol 2020 Sep 1;29(3):318-328. Epub 2020 Jun 1.

Huntsville Hospital for Women & Children, AL.

Purpose The purpose of this study was to construct and validate a recorded word recognition test for monolingual Spanish-speaking children utilizing a picture board and a picture-pointing task. Design The Spanish Pediatric Picture Identification Test was developed and validated in this study. Test construction steps included (a) producing new digital recordings of word lists created by Comstock and Martin (1984) using a bilingual Spanish-English female, (b) obtaining list equivalency, (c) creating digitally illustrated pictures representing the word lists, (d) validating the pictures using monolingual Spanish-speaking and bilingual Spanish-English children, and (e) re-establishing list equivalency and obtaining performance-intensity functions using a picture-pointing task with monolingual Spanish-speaking children and bilingual Spanish-English adults. Results Normative data for three Spanish word recognition lists were established. Performance-intensity functions at sensation levels from 0 to 40 dB SL in 8-dB steps were obtained, establishing list equivalency for Lists 1, 2, and 3. Conclusions The Spanish Pediatric Picture Identification Test was developed and validated as a picture-pointing task for word recognition with monolingual Spanish-speaking children. The two validated channel recordings include an English translation for ease of testing by clinicians lacking Spanish language skills. Future validation will be conducted with bilingual Spanish-English children with normal hearing and with hearing loss.
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http://dx.doi.org/10.1044/2020_AJA-19-00049DOI Listing
September 2020

Spanish Pediatric Speech Recognition Threshold Test.

Am J Audiol 2019 Sep 24;28(3):597-604. Epub 2019 Jul 24.

Mid-Shore Special Education Consortium, Easton, MD.

Purpose The purpose of this study was to construct a recorded speech recognition threshold (SRT) test for Spanish-speaking children utilizing a picture board and a picture-pointing task. Design The Spanish Pediatric Speech Recognition Threshold (SPSRT) test was developed and validated in this study. Test construction steps included (a) stimulus selection, (b) assessment of familiarity, (c) digital recording, (d) creation of pictures that accurately depicted the target word from the stimulus set, and (e) validation of the test and recordings. SRTs were obtained from 24 Spanish-speaking children whose 1st language was Spanish. Results Normative data are presented that validate the SPSRT and establish the baseline relationship between the pure-tone average and the SRT obtained with the SPSRT. Results indicated that the SPSRT obtained using this test should be within 2-12 dB of an individual's pure-tone average for Spanish-speaking children with normal hearing and minimal hearing loss. Conclusions The SPSRT was developed and validated as a picture-pointing Spanish SRT test to be used with Spanish-speaking children. The 2-channel recording contains an English translation track, making this test easy to administer and interpret for clinicians without knowledge of Spanish.
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http://dx.doi.org/10.1044/2019_AJA-18-0132DOI Listing
September 2019

Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

J Clin Oncol 2019 06 2;37(18):1566-1575. Epub 2019 May 2.

1 St Jude Children's Research Hospital, Memphis, TN.

Purpose: Sensorineural hearing loss (SNHL) is associated with intellectual and academic declines in children treated for embryonal brain tumors. This study expands upon existing research by examining core neurocognitive processes that may result in reading difficulties in children with treatment-related ototoxicity.

Patients And Methods: Prospectively gathered, serial, neuropsychological and audiology data for 260 children and young adults age 3 to 21 years (mean, 9.15 years) enrolled in a multisite research and treatment protocol, which included surgery, risk-adapted craniospinal irradiation (average risk, n = 186; high risk, n = 74), and chemotherapy, were analyzed using linear mixed models. Participants were assessed at baseline and up to 5 years after diagnosis and grouped according to degree of SNHL. Included were 196 children with intact hearing or mild to moderate SNHL (Chang grade 0, 1a, 1b, or 2a) and 64 children with severe SNHL (Chang grade 2b or greater). Performance on eight neurocognitive variables targeting reading outcomes (eg, phonemics, fluency, comprehension) and contributory cognitive processes (eg, working memory, processing speed) was analyzed.

Results: Participants with severe SNHL performed significantly worse on all variables compared with children with normal or mild to moderate SNHL ( ≤ .05), except for tasks assessing awareness of sounds and working memory. Controlling for age at diagnosis and risk-adapted craniospinal irradiation dose, performance on the following four variables remained significantly lower for children with severe SNHL: phonemic skills, phonetic decoding, reading comprehension, and speed of information processing ( ≤ .05).

Conclusion: Children with severe SNHL exhibit greater reading difficulties over time. Specifically, they seem to struggle most with phonological skills and processing speed, which affect higher level skills such as reading comprehension.
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http://dx.doi.org/10.1200/JCO.18.01358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599406PMC
June 2019

Treatment burden and long-term health deficits of patients with low-grade gliomas or glioneuronal tumors diagnosed during the first year of life.

Cancer 2019 04 8;125(7):1163-1175. Epub 2019 Jan 8.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Low-grade gliomas (LGGs) and low-grade glioneuronal tumors (LGGNTs) diagnosed during the first year of life carry unique clinical characteristics and challenges in management. However, data on the treatment burden, outcomes, and morbidities are lacking.

Methods: A retrospective study of LGGs and LGGNTs diagnosed in patients younger than 12 months at St. Jude Children's Research Hospital (1986-2015) was conducted.

Results: For the 51 patients (including 31 males), the mean age at diagnosis was 6.47 months (range, 0.17-11.76 months), and the mean follow-up period was 11.8 years (range, 0.21-29.19 years). Tumor locations were hypothalamic/optic pathway (61%), hemispheric (12%), brainstem (12%), cerebellar (8%), and spinal (8%). There were 41 patients with histological diagnoses: 28 had World Health Organization grade 1 tumors, 6 had grade 2 tumors, and 7 had an LGG/LGGNT not definitively graded. Forty-one patients required an active intervention at diagnosis. Throughout their treatment course, 41 patients eventually underwent tumor-directed surgeries (median, 2 surgeries; range, 1-6), 39 received chemotherapy (median, 2 regimens; range, 1-13), and 21 received radiotherapy. Forty patients experienced disease progression (median, 2 progressions; range, 1-18). Ten patients died of progression (n = 5), malignant transformation (n = 2), a second cancer (n = 2), or a shunt infection (n = 1). The 10-year overall survival, progression-free survival, and radiation-free survival rates were 85% ± 5.3%, 16.9% ± 5.3%, and 51.2% ± 7.5%, respectively. Forty-nine patients experienced health deficits (eg, endocrinopathies, obesity, seizures, visual/hearing impairments, neurocognitive impairments, and cerebrovascular disease). Predictors of progression and toxicities were defined.

Conclusions: Infantile LGG/LGGNT is a chronic, progressive disease universally associated with long-term morbidities and requires multidisciplinary intervention.
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http://dx.doi.org/10.1002/cncr.31918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420385PMC
April 2019

Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium.

Lancet Oncol 2019 01;20(1):e29-e41

Institute for Cancer Outcomes and Survivorship, Department of Pediatrics, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, AL, USA. Electronic address:

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.
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http://dx.doi.org/10.1016/S1470-2045(18)30858-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549756PMC
January 2019

Neuropsychological outcomes of patients with low-grade glioma diagnosed during the first year of life.

J Neurooncol 2019 Jan 22;141(2):413-420. Epub 2018 Nov 22.

Department of Psychology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA.

Purpose: Low-grade gliomas (LGG) are a heterogeneous group of brain tumors, which are often assumed to have a benign course. Yet, children diagnosed and treated for LGG in infancy are at increased risk for neurodevelopmental disruption. We sought to investigate neuropsychological outcomes of infants diagnosed with LGG.

Methods: Between 1986 and 2013, 51 patients were diagnosed with LGG before 12 months of age and managed at St. Jude Children's Research Hospital. Twenty-five of the 51 patients received a cognitive assessment (68% male; 6.8 ± 3.3 months at diagnosis; 10.5 ± 4.8 years at latest assessment). Approximately half the patients received radiation therapy (n = 12; aged 4.0 ± 3.0 years at radiation therapy), with a median of 2 chemotherapy regimens (range = 0-5) and 1 tumor directed surgery (range = 0-5).

Results: The analyses revealed performance below age expectations on measures of IQ, memory, reading, mathematics, and fine motor functioning as well as parent-report of attention, executive, and adaptive functioning. Following correction for multiple comparisons, a greater number of chemotherapy regimens was associated with lower scores on measures of IQ and mathematics. More tumor directed surgeries and presence of visual field loss were associated with poorer dominant hand fine motor control. Radiation therapy exposure was not associated with decline in neuropsychological performance.

Conclusions: Children diagnosed with LGG in infancy experience substantial neuropsychological deficits. Treatment factors, including number of chemotherapy regimens and tumor directed surgeries, may increase risk for neurodevelopmental disruption and need to be considered in treatment planning.
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http://dx.doi.org/10.1007/s11060-018-03048-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344293PMC
January 2019

Auditory Outcomes in Patients Who Received Proton Radiotherapy for Craniopharyngioma.

Am J Audiol 2018 Sep;27(3):306-315

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN.

Purpose: Compared to photon-based radiotherapy, protons deliver less radiation to healthy tissue resulting in the potential reduction of late complications such as sensorineural hearing loss (SNHL). We report early auditory outcomes in children treated with proton radiotherapy (PRT) for craniopharyngioma.

Method: Conventional frequency (CF = 0.25-8.0 kHz) audiometry, extended high-frequency (EHF = 9.0-16.0 kHz) audiometry, distortion product otoacoustic emission (DPOAE) testing, and speech-in-noise (SIN) assessments were prospectively and longitudinally conducted on 74 children with a median of 2 post-PRT evaluations (range, 1-5) per patient. The median age at PRT initiation was 10 years, and median follow-up time was 2 years. Ototoxicity was classified using the Chang Ototoxicity Grading Scale (Chang & Chinosornvatana, 2010) and the American Speech-Language-Hearing Association (ASHA) criteria (ASHA, 1994). Comparisons were made between baseline and most recent DPOAE levels, with evidence of ototoxicity based on criterion reductions of ≥ 6 dB. The critical difference values for comparing SIN scores between two conditions (i.e., pre- and post-PRT) were used to determine a significant change between test scores.

Results: At last evaluation, no patients had SNHL in the CF range, and 2 patients had SNHL (Chang Grade 1a) in the EHF range. Based on the ASHA criteria, a decrease in hearing was observed in 0 patients in the CF range alone, in 9 patients in the EHF range alone, and in 15 patients in both the CF and EHF ranges. DPOAE levels decreased at a faster rate at higher versus lower frequencies. For 41 evaluable patients, SIN perception did not decline over time (p = .6463).

Conclusion: At a median follow-up time of 2 years post-PRT, normal hearing was maintained within the CF range. However, subclinical decreases in hearing were observed, particularly in the EHF range and in the DPOAE level; thus, long-term follow-up is recommended to monitor for potential auditory late effects from PRT.
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http://dx.doi.org/10.1044/2018_AJA-18-0026DOI Listing
September 2018

Profound hearing loss following surgery in pediatric patients with posterior fossa low-grade glioma.

Neurooncol Pract 2018 May 18;5(2):96-103. Epub 2017 Dec 18.

Department of Pediatric Medicine, Division of Neurology, St. Jude Children's Research Hospital, USA.

Background: Hearing loss may occur in patients with posterior fossa low-grade glioma who undergo surgery.

Methods: We retrospectively reviewed 217 patients with posterior fossa low-grade glioma, including 115 for whom results of hearing tests performed after surgery and before chemotherapy or radiation therapy were available. We explored the association of UHL with age at diagnosis, sex, race, tumor location, extent of resection, posterior fossa syndrome, ventriculoperitoneal shunt placement, and histology.

Results: Of the 115 patients, 15 (13.0%: 11 male, 6 black, 8 white, 1 multiracial; median age 7 years [range, 1.3-17.2 years]) had profound UHL after surgery alone or before receiving ototoxic therapy. Median age at tumor diagnosis was 6.8 years (range, 0.7-14.1 years), and median age at surgery was 6.8 years (range, 0.7-14.1 years). Patients with UHL had pathology characteristic of pilocytic astrocytoma (n = 10), ganglioglioma (n = 4), or low-grade astrocytoma (n = 1). Of these 15 patients, 4 underwent biopsy, 1 underwent gross total resection, 1 underwent near-total resection, and 9 underwent subtotal resection. UHL was more frequent in black patients than in white patients (OR 7.3, = .007) and less frequent in patients who underwent gross total resection or near-total resection than in those who underwent subtotal resection (OR 0.11, = .02).

Conclusions: Children undergoing surgery for posterior fossa low-grade glioma are at risk for UHL, which may be related to race or extent of resection. These patients should receive postoperative audiologic testing, as earlier intervention may improve outcomes.
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http://dx.doi.org/10.1093/nop/npx025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946892PMC
May 2018

Approach for Classification and Severity Grading of Long-term and Late-Onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort.

Cancer Epidemiol Biomarkers Prev 2017 05 29;26(5):666-674. Epub 2016 Dec 29.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. .
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413397PMC
May 2017

Evaluation and Management of Hearing Loss in Survivors of Childhood and Adolescent Cancers: A Report From the Children's Oncology Group.

Pediatr Blood Cancer 2016 Jul 29;63(7):1152-62. Epub 2016 Feb 29.

Pediatric Hematology-Oncology, Baystate Medical Center, Springfield, Massachusetts.

Hearing loss (HL) is common in childhood cancer survivors exposed to platinum chemotherapy and/or cranial radiation and can severely impact quality of life. Early detection and appropriate management can mitigate academic, speech, language, social, and psychological morbidity resulting from hearing deficits. This review is targeted as a resource for providers involved in aftercare of childhood cancers. The goal is to promote early identification of survivors at-risk for HL, appropriate evaluation and interpretation of diagnostic tests, timely referral to an audiologist when indicated, and to increase knowledge of current therapeutic options.
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http://dx.doi.org/10.1002/pbc.25951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520626PMC
July 2016

Hearing Loss in Patients Who Received Cranial Radiation Therapy for Childhood Cancer.

J Clin Oncol 2016 Apr 25;34(11):1248-55. Epub 2016 Jan 25.

Johnnie K. Bass, Chia-Ho Hua, Jie Huang, Arzu Onar-Thomas, Kirsten K. Ness, Skye Jones, Stephanie White, Shaum P. Bhagat, and Thomas E. Merchant, St Jude Children's Research Hospital; Johnnie K. Bass and Shaum P. Bhagat, University of Memphis, Memphis TN; and Kay W. Chang, Stanford University, Stanford, CA.

Purpose: Patients treated with cranial radiation therapy (RT) are at risk for sensorineural hearing loss (SNHL). Although SNHL is often characterized as a delayed consequence of anticancer therapy, longitudinal reports of SNHL in childhood cancer survivors treated with contemporary RT are limited. We report the incidence, onset, severity, and long-term trajectory of SNHL among children receiving RT. Potential risk factors for SNHL were also identified.

Patients And Methods: Serial audiologic testing was conducted on 235 pediatric patients who were treated with conformal or intensity-modulated RT as part of an institutional phase II trial for localized primary brain tumors, including craniopharyngioma, ependymoma, and juvenile pilocytic astrocytoma. All but one patient had measurable cochlear radiation dose (CRD) greater than 0 Gy. The median follow-up from RT initiation to latest audiogram was 9 years with a median of 11 post-RT audiograms per patient. Audiograms were classified by the Chang Ototoxicity Grading Scale. Progression was defined by an increase in Chang grade from SNHL onset to the most recent evaluation.

Results: At last evaluation, SNHL was prevalent in 14% of patients: 2.1% had mild and 11.9% had significant SNHL requiring hearing aids. Median time from RT to SNHL onset was 3.6 years (range, 0.4 to 13.2 years). Among 29 patients with follow-up evaluations after SNHL onset, 65.5% experienced continued decline in hearing sensitivity in either ear and 34.5% had no change. Younger age at RT initiation (hazard ratio [HR], 2.32; 95% CI, 1.21 to 4.46), higher CRD (HR, 1.07; 95% CI, 1.03 to 1.11), and cerebrospinal fluid shunting (HR, 2.02; 95% CI, 1.07 to 3.78) were associated with SNHL.

Conclusion: SNHL is a late effect of RT that likely worsens over time. Long-term audiologic follow-up for a minimum of 10 years post-RT is recommended.
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http://dx.doi.org/10.1200/JCO.2015.63.6738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933129PMC
April 2016

Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study.

Cancer 2015 Nov 19;121(22):4053-61. Epub 2015 Aug 19.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Survivors of childhood cancer who are treated with platinum-based chemotherapy and/or cranial radiation are at risk of treatment-induced hearing loss. However, the effects of such hearing loss on adult social attainment have not been well elucidated.

Methods: Adult survivors of pediatric central nervous system (CNS) solid tumors (180 survivors) and non-CNS solid tumors (226 survivors) who were treated with potentially ototoxic cancer therapy completed audiologic evaluations and questionnaires assessing their perception of social functioning and social attainment (ie, independent living, marriage, and employment). Audiograms were graded with the Chang ototoxicity grading scale. Analyses were stratified by tumor type (ie, CNS vs non-CNS). Multivariable logistic regression models were conducted with adjustment for age; sex; chronic health conditions; and, for the CNS group, IQ. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported.

Results: Serious hearing loss (that requiring a hearing aid or deafness) was detected in 36% of survivors of CNS tumors and 39% of survivors of non-CNS tumors. Serious hearing loss was associated with an increased risk of perceived negative impact in ≥1 areas of social functioning (survivors of non-CNS tumors: OR, 1.83 [95% CI, 1.00-3.34]). Among survivors of non-CNS tumors, serious hearing loss was associated with 2-fold increased risk of nonindependent living (OR, 2.19; 95% CI, 1.19-4.04) and unemployment or not graduating from high school (OR, 1.85; 95% CI, 1.00-3.34).

Conclusions: A substantial proportion of adult survivors of childhood cancer treated with potentially ototoxic therapy have serious hearing loss. Treatment-induced hearing loss was found to be associated with reduced social attainment, both perceived and actual, in this study sample.
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http://dx.doi.org/10.1002/cncr.29604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635051PMC
November 2015

Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss.

Nat Genet 2015 Mar 9;47(3):263-6. Epub 2015 Feb 9.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10(-8), hazard ratio = 4.5) in 238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents.
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http://dx.doi.org/10.1038/ng.3217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358157PMC
March 2015

Challenges in ototoxicity monitoring in the pediatric oncology population.

J Am Acad Audiol 2014 Sep;25(8):760-74; quiz 782-3

University of Memphis, Hearing Science Laboratory, School of Communication Sciences and Disorders, Memphis, TN; St. Jude Children's Research Hospital, Rehabilitation Services, Memphis, TN.

Background: Platinum-based chemotherapy and cranial radiation are effective treatment options commonly prescribed for a variety of childhood cancers. These therapies can, and often do, result in early- and late-onset adverse health effects such as hearing loss. Undetected hearing loss is particularly concerning in young children developing speech and language skills and can negatively affect academic achievement and the psychosocial well-being of both young and older children. Early detection of hearing loss in pediatric oncology patients and early intervention are critical to help these patients succeed in achieving these developmental milestones.

Purpose: The primary goal of this study was to create a tutorial for audiologists concerning the monitoring of ototoxicity in the pediatric oncology population. Monitoring hearing for children receiving potentially ototoxic cancer treatments presents special issues and challenges for audiologists. This tutorial will orient the reader to these special issues and challenges, and potential solutions will be proposed.

Design: This tutorial is organized into sections, including an overview of platinum compound and cranial radiation treatments commonly used to treat pediatric cancer, modifications of the test battery required to appropriately monitor for ototoxic hearing loss in children, a proposal for a monitoring protocol, and descriptions of the grading scales that are frequently used by oncologists to determine the severity of ototoxic hearing loss.

Conclusions: Identification of ototoxicity is crucial in children receiving cancer treatments because of the impact that acquired hearing loss has on social and educational outcomes in the developing child. Monitoring hearing in children presents challenges that are unique to this population. Much effort has been put forth in developing and validating the International Society of Pediatric Oncology ototoxicity grading scale for international use in reporting auditory outcomes in clinical trials. In the future, the development of standardized monitoring protocols will assist audiologists in providing optimal care to children treated for cancer.
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http://dx.doi.org/10.3766/jaaa.25.8.6DOI Listing
September 2014

Concordance between the chang and the International Society of Pediatric Oncology (SIOP) ototoxicity grading scales in patients treated with cisplatin for medulloblastoma.

Pediatr Blood Cancer 2014 Apr 1;61(4):601-5. Epub 2013 Nov 1.

Rehabilitation Services, St. Jude Children's Research Hospital, Memphis, Tennessee; School of Communication Sciences and Disorders, University of Memphis, Memphis, Tennessee.

Background: 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.

Procedures: 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/m(2) 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1002/pbc.24830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371725PMC
April 2014

Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma.

Neuro Oncol 2014 Aug 3;16(8):1129-36. Epub 2014 Feb 3.

Department of Psychology St. Jude Children's Research Hospital, Memphis, Tennessee (J.E.S., S.L.P.); Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee (J.G.G.); School of Public Health, University of Memphis, Memphis, Tennessee (J.G.G.); Rehabilitation Services, St. Jude Children's Research Hospital, Memphis, Tennessee (J.K.B); Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee (M.W., S.C., H.Z.); Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (A.G.); Royal Children's Hospital Brisbane, Herston, Australia (M.S.); Department of Pediatric Medicine, Texas Children's Hospital, Houston, Texas (M.L.C.); Department of Psychiatry, Duke University Medical Center, Durham, North Carolina (M.J.B.); Department of Psychology, The Hospital for Sick Children, Toronto, Canada (D.J.M.); Department of Psychology, The Royal Children's Hospital Melbourne, Victoria Australia (S.J.K.); Neuro-Oncology Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (C.L.A); Psychology Service, Sydney Children's Hospital, Randwick, Australia (R.B.).

Background: The aim of this study was to prospectively examine the effects of hearing loss and posterior fossa syndrome (PFS), in addition to age at diagnosis and disease risk status, on change in intellectual and academic outcomes following diagnosis and treatment in a large sample of medulloblastoma patients.

Methods: Data from at least 2 cognitive and academic assessments were available from 165 patients (ages 3-21 years) treated with surgery, risk-adapted craniospinal irradiation, and 4 courses of chemotherapy with stem cell support. Patients underwent serial evaluation of cognitive and academic functioning from baseline up to 5 years post diagnosis.

Results: Serious hearing loss, PFS, younger age at diagnosis, and high-risk status were all significant risk factors for decline in intellectual and academic skills. Serious hearing loss and PFS independently predicted below-average estimated mean intellectual ability at 5 years post diagnosis. Patients with high-risk medulloblastoma and young age at diagnosis (<7 years) exhibited the largest drop in mean scores for intellectual and academic outcomes.

Conclusions: Despite a significant decline over time, intellectual and academic outcomes remained within the average range at 5 years post diagnosis for the majority of patients. Future studies should determine if scores remain within the average range at time points further out from treatment. Patients at heightened risk should be closely monitored and provided with recommendations for appropriate interventions.
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http://dx.doi.org/10.1093/neuonc/nou006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096173PMC
August 2014

Evaluation of amifostine for protection against cisplatin-induced serious hearing loss in children treated for average-risk or high-risk medulloblastoma.

Neuro Oncol 2014 Jun 10;16(6):848-55. Epub 2014 Jan 10.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis Tenneessee (J.G.G., G.T.A.); Department of Rehabilitation Service, St. Jude Children's Research Hospital, Memphis Tenneessee (J.K.B.); Department of Biostatistics, St. Jude Children's Research Hospital, Memphis Tenneessee (A.O.-T., J.H.); Department of Oncology, St. Jude Children's Research Hospital, Memphis Tenneessee (C.W., I.Q., G.T.A., A.B., A.G.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis Tenneessee, (A.P.P., T.E.M.); Department of Bone Marrow Transplantation, St. Jude Children's Research Hospital, Memphis, Tenneessee (A.S.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis Tenneessee (C.F.S.); Department of Pediatrics, Texas Children's Cancer Center, Houston, Texas (M.C.); Hospital for Sick Children, Toronto, Ontario, Canada (E.B.); Royal Children's Hospital Brisbane, Herston, Australia (T.H.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (S.G.); The Royal Children's Hospital Melbourne, Victoria, Australia (J.A.H.); Children's Hospital at Westmead, Sydney, Australia (S.K.); Sydney Children's Hospital, Sydney, Australia (R.C.); Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); School of Public Health, University of Memphis, Memphis, Tenneessee (J.G.G.).

Background: The purpose of this study was to evaluate amifostine for protection from cisplatin-induced serious hearing loss in patients with average-risk medulloblastoma by extending a previous analysis to a much larger sample size. In addition, this study aimed to assess amifostine with serious hearing loss in patients with high-risk medulloblastoma treated with cisplatin.

Methods: Newly diagnosed medulloblastoma patients (n = 379; ages 3-21 years), enrolled on one of 2 sequential St. Jude clinical protocols that included 4 courses of 75 mg/m(2) cisplatin, were compared for hearing loss by whether or not they received 600 mg/m(2) of amifostine immediately before and 3 hours into each cisplatin infusion. Amifostine administration was not randomized. The last audiological evaluation between 5.5 and 24.5 months following protocol treatment initiation was graded using the Chang Ototoxicity Scale. A grade of ≥ 2b (loss requiring a hearing aid or deafness) was considered a serious event.

Results: Among average-risk patients (n = 263), amifostine was associated with protection from serious hearing loss (adjusted OR, 0.30; 95% CI, 0.14-0.64). For high-risk patients (n = 116), however, there was not sufficient evidence to conclude that amifostine prevented serious hearing loss (OR, 0.89; 95% CI, 0.31-2.54).

Conclusions: Although patients in this study were not randomly assigned to amifostine treatment, we found evidence in favor of amifostine administration for protection against cisplatin-induced serious hearing loss in average-risk but not in high-risk, medulloblastoma patients.
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http://dx.doi.org/10.1093/neuonc/not241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022215PMC
June 2014

Carboplatin-associated ototoxicity in children with retinoblastoma.

J Clin Oncol 2012 Apr 27;30(10):1034-41. Epub 2012 Feb 27.

St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.

Purpose: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1200/JCO.2011.36.9744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341147PMC
April 2012

Monitoring carboplatin ototoxicity with distortion-product otoacoustic emissions in children with retinoblastoma.

Int J Pediatr Otorhinolaryngol 2010 Oct 29;74(10):1156-63. Epub 2010 Jul 29.

School of Audiology and Speech-Language Pathology, The University of Memphis, Memphis, TN, United States.

Objective: Carboplatin is a common chemotherapy agent with potential ototoxic side effects that is used to treat a variety of pediatric cancers, including retinoblastoma. Retinoblastoma is a malignant tumor of the retina that is usually diagnosed in young children. Distortion-product otoacoustic emission tests offer an effective method of monitoring for ototoxicity in young children. This study was designed to compare measurements of distortion-product otoacoustic emissions obtained before and after several courses of carboplatin chemotherapy in order to examine if (a) mean distortion-product otoacoustic emission levels were significantly different; and (b) if criterion reductions in distortion-product otoacoustic emission levels were observed in individual children.

Methods: A prospective repeated measures study. Ten children with a median age of 7.6 months (range, 3-72 months) diagnosed with unilateral or bilateral retinoblastoma were examined. Distortion-product otoacoustic emissions were acquired from both ears of the children with 65/55 dB SPL primary tones (f(2)=793-7996 Hz) and a frequency resolution of 3 points/octave. Distortion-product otoacoustic emission levels in dB SPL were measured before chemotherapy treatment (baseline measurement) and after 3-4 courses of chemotherapy (interim measurement). Comparisons were made between baseline and interim distortion-product otoacoustic emission levels (collapsed across ears). Evidence of ototoxicity was based on criterion reductions (≥ 6 dB) in distortion-product otoacoustic emission levels.

Results: Significant differences between baseline and interim mean distortion-product otoacoustic emission levels were only observed at f(2) = 7996 Hz. Four children exhibited criterion reductions in distortion-product otoacoustic emission levels.

Conclusions: Mean distortion-product otoacoustic emission levels at most frequencies were not changed following 3-4 courses of carboplatin chemotherapy in children with retinoblastoma. However, on an individual basis, children receiving higher doses of carboplatin exhibited criterion reductions in distortion-product otoacoustic emission level at several frequencies. These findings suggest that higher doses of carboplatin affect outer hair cell function, and distortion-product otoacoustic emission tests can provide useful information when monitoring children at risk of developing carboplatin ototoxicity.
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http://dx.doi.org/10.1016/j.ijporl.2010.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4787621PMC
October 2010

Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose.

Int J Radiat Oncol Biol Phys 2008 Nov 18;72(3):892-9. Epub 2008 Apr 18.

Division of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Purpose: To determine the effect of cochlear dose on sensorineural hearing loss in pediatric patients with brain tumor treated by using conformal radiation therapy (CRT).

Patients And Methods: We studied 78 pediatric patients (155 ears) with localized brain tumors treated in 1997-2001 who had not received platinum-based chemotherapy and were followed up for at least 48 months. They were evaluated prospectively by means of serial pure-tone audiograms (250 Hz-8 kHz) and/or auditory brainstem response before and every 6 months after CRT.

Results: Hearing loss occurred in 14% (11 of 78) of patients and 11% (17 of 155) of cochleae, with onset most often at 3-5 years after CRT. The incidence of hearing loss was low for a cochlear mean dose of 30 Gy or less and increased at greater than 40-45 Gy. Risk was greater at high frequencies (6-8 kHz). In children who tested abnormal for hearing, average hearing thresholds increased from a less than 25 decibel (dB) hearing level (HL) at baseline to a mean of 46 +/- 13 (SD) dB HL for high frequencies, 41 +/- 7 dB HL for low frequencies, and 38 +/- 6 dB HL for intermediate frequencies.

Conclusions: Sensorineural hearing loss is a late effect of CRT. In the absence of other factors, including ototoxic chemotherapy, increase in cochlear dose correlates positively with hearing loss in pediatric patients with brain tumor. To minimize the risk of hearing loss for children treated with radiation therapy, a cumulative cochlear dose less than 35 Gy is recommended for patients planned to receive 54-59.4 Gy in 30-33 treatment fractions.
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http://dx.doi.org/10.1016/j.ijrobp.2008.01.050DOI Listing
November 2008