Publications

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    ABSTRACT: 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/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. 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. Pediatr Blood Cancer 2014;61:601-605. © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 04/2014; 61(4):601-5. · 2.35 Impact Factor
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    Chapter: Ototoxicity
    Kay W Chang
    01/2014: pages 2542-2555;
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    Stephen R Hoff, Kay W Chang
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    ABSTRACT: To describe a novel technique for removal of embedded distal airway foreign bodies with emphasis on procedural steps and management. The proximal bronchoplasty retrieval (PBR) technique is described including indications, rationale, surgical technique, and clinical decision making. Two representative cases are described in detail in order to demonstrate the technique. The PBR technique was successfully used to remove the two described embedded distal airway foreign bodies after other attempts had failed. Airway foreign bodies which have been present for several days or weeks are associated with edema and granulation tissue which often embeds the foreign body and may prevent removal due to proximal airway narrowing. We present a novel technique using endoscopic balloon dilation bronchoplasty to enlarge the airway proximal to the foreign body and enable removal with two example cases presented herein. The PBR technique allowed for removal of otherwise "stuck" distal airway foreign bodies.
    International journal of pediatric otorhinolaryngology 11/2013; · 0.85 Impact Factor
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    ABSTRACT: To perform a systematic review, comparing hearing outcomes of atresiaplasty versus osseointegrated bone conduction device (OBCD) in congenital aural atresia (CAA) patients. Approximately 107 studies, published from 1975 to 2012, evaluating hearing outcomes after atresiaplasty and/or OBCD in CAA patients were identified through a PubMed search. Articles that evaluated external auditory canal stenosis alone, did not report speech reception threshold (SRT), pure tone average (PTA), hearing gain, or air-bone gap (ABG) or had less than 5 patients were excluded. For authors or institutions with multiple reports, the largest or most recent study was included. Forty-one articles satisfied our inclusion and exclusion criteria. The number and percentage of ears with a postoperative SRT, PTA, ABG less than 30 dB, and/or average hearing gain were extracted. The total number of ears and the timing of the postoperative audiogram were also noted. Of the atresiaplasty ears, 73.8% (95% CI, 62.2%-85.4%), had a SRT less than 30 dB (338 ears), 60.3% (95% CI, 45.8%-74.8%) had a PTA less than 30 dB (390 ears), and 68.9% (95% CI, 59.4%-78.3%) had an ABG less than 30 dB (852 ears). The average hearing gain was 24.1 dB (95% CI, 21.62-26.51) for 516 ears. Hearing outcomes deteriorated with time. Of OBCD patients, 95.9% (95% CI, 91.5%-100.0%) had a PTA less than 30 dB (77 ears), and 98.2% (95% CI, 94.5%-100.0%) had an ABG less than 30 dB (47 ears); the average hearing gain was 38.0 dB (95% CI, 33.14-45.22) in 100 ears. The OBCD has better hearing outcomes compared with atresiaplasty in patients with CAA.
    Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 09/2013; · 1.44 Impact Factor
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    Dylan K Chan, Kay W Chang
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    ABSTRACT: To perform a systematic review of GJB2-associated hearing loss to describe genotype distributions and auditory phenotype. 230 primary studies identified from Pubmed REVIEW METHODS: Pubmed was searched systematically to screen broadly for any study reporting on genotype and carrier frequencies for biallelic GJB2-associated hearing loss in defined populations around the world. Genotype and audiometric data were extracted and subjected to meta-analysis to determine genotype distributions, carrier frequencies, rates of asymmetric or progressive hearing loss, and imaging abnormalities. 216 articles comprising over 43,000 hearing-loss probands were included. The prevalence of biallelic GJB2-associated hearing loss was consistent across most of the 63 countries examined, with different mutations being predominant in different countries. Common mutations were found in greater than 3% of the general population worldwide. Meta-analysis of 48 case-control studies demonstrated a two-fold higher carrier frequency among hearing-impaired individuals compared to normal-hearing controls for truncating alleles, but not V37I. Progression, asymmetry, and imaging abnormalities were present in 14-19% of individuals with GJB2-associated hearing loss. GJB2 mutations are highly prevalent around the world. The multiple predominant mutations present in different populations attests to the importance of this gene for normal cochlear function and suggests an evolutionary heterozygote advantage. The unusually high carrier rate for truncating mutations among hearing-impaired individuals is consistent with either the presence of complementary mutations or a carrier phenotype. The significant rate of asymmetry and progression highlights the importance of diagnostic workup and close follow-up for this highly variable condition. Laryngoscope, 2013.
    The Laryngoscope 07/2013; · 1.98 Impact Factor
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    Kevin C Huoh, Kay W Chang
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    ABSTRACT: IMPORTANCE Isotretinoin is frequently prescribed for the treatment of acne vulgaris. Among the numerous documented adverse effects, most common are xerostomia and cheilitis. Lip abscesses as a consequence of cheilitis present dramatically and may pose a diagnostic challenge. OBSERVATIONS We present a case of a 15-year-old boy with a severe lip abscess requiring incision and drainage and hospital admission for intravenous antibiotic treatment of methicillin-resistant Staphylococcus aureus. We discuss the pathophysiologic characteristics of isotretinoin therapy and the likely causative role that the medication played in the development of the lip abscess. CONCLUSIONS AND RELEVANCE Although rare, lip abscesses related to isotretinoin therapy present with substantial morbidity and should be promptly recognized. Misdiagnosis of mucositis and angioedema may delay appropriate therapy.
    JAMA dermatology (Chicago, Ill.). 06/2013;
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    ABSTRACT: Purpose 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, audiolo-gists, and neurosurgeons to develop and advance research and clinical trials for otoprotection. Results 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. Conclusion 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.
    Journal of Clinical Oncology 07/2012; 30(19):2408-2417. · 18.04 Impact Factor
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    ABSTRACT: Propranolol has recently emerged as an effective therapy for infantile hemangiomas causing regression. The β-adrenergic receptor (AR) antagonist is thought to cause vasoconstriction by its effect on nitric oxide, block angiogenesis by its effect on vascular endothelial growth factor (VEGF), and induce apoptosis. In a prior report, we identified expression of β2-AR (B2-AR) and its phosphorylated form (B2-ARP) in a case of infantile hemangioma that responded to propranolol treatment. We now explore the expression of βARs on a variety of vascular lesions utilizing a tissue microarray containing 141 lesions, including infantile hemangiomas, angiosarcomas, hemangiomas, hemangioendotheliomas, and various vascular malformations. The array was immunostained for B2-AR, B2-ARP, and β3-AR (B3-AR), and the results scored for the intensity of endothelial cell expression as negative, weak positive, or strong positive. All phases of infantile hemangiomas had strong expression of all three receptors, with the exception of only weak expression of B2-ARP in the proliferative phase infantile hemangioma. Strong expression of all three receptors was present in many hemangiomas, hemangioendotheliomas, and vascular malformations. Absent to weak expression of all three receptors was seen in glomus tumor, hobnail hemangioendothelioma, pyogenic granuloma, and reactive vascular proliferations. This is the first study to report β-AR expression in a variety of vascular lesions. Although immunohistochemical expression of the receptors does not necessarily indicate that similar pathways of responsiveness to β-blockade are present, it does raises the possibility that β-blockade could potentially affect apoptosis and decrease responsiveness to VEGF. Additional study is warranted, as therapeutic options are limited for some patients with these lesions.Modern Pathology advance online publication, 29 June 2012; doi:10.1038/modpathol.2012.108.
    Modern Pathology 06/2012; · 5.25 Impact Factor
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    ABSTRACT: Many guidelines for reporting hearing results use the threshold at 3 kilohertz (kHz), a frequency not measured routinely. This study assessed the validity of estimating the missing 3-kHz threshold by averaging the measured thresholds at 2 and 4 kHz. The estimated threshold was compared to the measured threshold at 3 kHz individually and when used in the pure-tone average (PTA) of 0.5, 1, 2, and 3 kHz in audiometric data from 2170 patients. The difference between the estimated and measured thresholds for 3 kHz was within ± 5 dB in 72% of audiograms, ± 10 dB in 91%, and within ± 20 dB in 99% (correlation coefficient r = 0.965). The difference between the PTA threshold using the estimated threshold compared with using the measured threshold at 3 kHz was within ± 5 dB in 99% of audiograms (r = 0.997). The estimated threshold accurately approximates the measured threshold at 3 kHz, especially when incorporated into the PTA.
    Otolaryngology Head and Neck Surgery 02/2012; 147(1):102-4. · 1.73 Impact Factor
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    Kay W Chang
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    ABSTRACT: To design a grading scale and audiologic protocols to better reflect clinical impact than the currently widely used classifications. Retrospective. Audiologic studies from 130 patients receiving cisplatin chemotherapy were analyzed. Pure-tone audiograms were evaluated using the newly proposed grading criteria, Brock criteria, and Common Terminology Criteria for Adverse Events (CTCAE). The resulting grades were then compared to recommended audiologic interventions. Auditory brainstem response (ABR) data and data on incidences of conductive hearing loss from other multi-institutional studies that the author participated in were compared to data from this cohort. Although the newly proposed, Brock, and CTCAE ototoxicity grades were significantly related to audiologist recommendations for assistive devices (P < .0001), the newly proposed criteria were more specific and allowed better delineation of different patients into distinct subgroups requiring either FM system (grade 2a) or hearing aid (grade 2b or higher). Multi-institutional data review indicated significant problems with ABR evaluations and separating out conductive hearing losses from ototoxicity. The newly proposed grading system needs to be paired with specific recommendations regarding audiologic monitoring protocols as well as active participation by the audiologists implementing the protocol to provide clinically accurate assessment and grading of ototoxicity.
    The Laryngoscope 12/2011; 121(12):2649-57. · 1.98 Impact Factor
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    M C Mori, K W Chang
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    ABSTRACT: CH measurements can often be useful in the diagnosis of inner ear malformations associated with SNHL. Our aim was to establish the relationship between CH and age by using analysis of CT images in patients who underwent coronal CT scans of the temporal bone between 2001 and 2007. We measured CH on coronal CT scans of the temporal bone of 422 ears scanned from 2001 to 2007 in 211 patients, 1 month to 23 years of age. Using multivariate linear regression analysis, we determined the relationship of CH to age, sex, and HL type. In addition, 11 patients with multiple scans at different ages were assessed for change in CH with age. Average CH was 5.3 mm (normal range, 4.4-6.2 mm). Analysis showed no statistically significant change in CH across ages from 1 month to 23 years (95% CI for regression line slope = -0.003, 0.013). Likewise, there were no statistically significant differences in CH for patients with multiple scans at different ages. ICW increased with age as expected with increased cranial size. A small difference in CH between sexes was noted with males having greater CHs than females (P < .01). All patients with hypoplastic cochleas, defined by a CH <2 SDs from the mean (4.48 mm for males and 4.25 mm for females), had HL with a positive predictive value of 86%. CH does not change from 1 month of age to adulthood and is slightly greater in males than in females.
    American Journal of Neuroradiology 09/2011; 33(1):119-23. · 3.17 Impact Factor
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    ABSTRACT: Wegener's granulomatosis (WG) classically affects the upper and lower respiratory tracts as well as the renal system, while central nervous system (CNS) involvement is rare. We report a 17-year-old patient with WG who presented with a 2-month history of meningeal signs, left Horner's syndrome, multiple cranial neuropathies and a left middle ear effusion. MRI demonstrated left middle ear and mastoid effusions, pachymeningitis with diffuse left temporal dural enhancement, and right sinus destructive changes. In this report, we will review diagnostic and therapeutic approaches to Wegener's granulomatosis, with a particular emphasis on CNS manifestations and the adolescent population.
    International Journal of Pediatric Otorhinolaryngology Extra 01/2011; 6(2):80-84.
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    ABSTRACT: Diagnostic yield on GJB2 sequencing and computed tomography in the workup for idiopathic congenital sensorineural hearing loss is related to patient ethnicity. GJB2 sequencing and computed tomography of the temporal bones are important initial diagnostic tests in the workup of idiopathic congenital sensorineural hearing loss. Previous studies showed an association between mild or unilateral hearing loss and positive imaging findings and between severe or bilateral deafness and GJB2 mutations. Recent studies on connexin 26-associated deafness demonstrate a wide range of phenotypes that vary with ethnicity. We present a retrospective case series of 271 consecutive ethnically diverse patients evaluated for idiopathic congenital sensorineural hearing loss. Results of genetic testing and imaging were correlated with audiologic findings and ethnicity. All patients with asymmetric hearing loss had more positive findings on imaging. With respect to the severity of hearing loss, however, differences were noted between ethnic groups. Whereas white patients conformed to previous findings, Hispanics with severe hearing loss had similar rates of positive imaging and genetic testing results. Asians with mild hearing loss had significantly greater yield on genetic testing rather than on imaging. This reflects the high prevalence of the p.V37I mutation in GJB2 among Asians, which gives rise to a mild, frequently progressive phenotype. Ethnicity should be considered when determining the optimal sequence of diagnostic testing for idiopathic congenital sensorineural hearing loss. Asian patients, in particular, should all be screened for mutations in GJB2, especially in the case of mild hearing loss.
    Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 10/2010; 32(1):81-7. · 1.44 Impact Factor
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    ABSTRACT: (1) To present six patients with symptomatic airway hemangiomas treated with oral propranolol. (2) To review the diagnostic and treatment options for airway hemangiomas and propose a new management protocol. Retrospective review. Tertiary care children's hospital. Pediatric patients diagnosed with obstructive airway hemangiomas treated with oral propranolol. Patients were followed for symptomatic improvement and relief of airway obstruction on imaging or laryngoscopy. Seven patients presenting with airway obstruction were treated with propranolol. One patient had a focal hemangioma confined to the subglottis. Four patients had airway hemangiomas that extended beyond the confines of the larynx and trachea. A sixth patient had a bulky supraglottic hemangioma. A seventh patient with an extensive maxillofacial lesion failed propranolol therapy and was found to have a pyogenic granuloma on final pathology after excision. Six patients had failed standard medical therapy and/or surgical interventions and were treated successfully with oral propranolol with improvements in airway symptoms and oral intake, requiring no further surgical intervention. Treatment was initiated as early as 1.5 months of age, and as late as 22 months. No adverse side effects of propranolol were noted. Oral propranolol was successfully used to treat airway hemangiomas, resulting in rapid airway stabilization, obviating the need for operative intervention, and reducing the duration of systemic corticosteroid therapy while causing no obvious adverse effects. These outstanding results enable the possibility of use of a standardized diagnostic and treatment algorithm for airway hemangiomas that incorporates systemic propranolol.
    International journal of pediatric otorhinolaryngology 09/2010; 74(9):1043-8. · 0.85 Impact Factor
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    Kay W Chang, Nina Chinosornvatana
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    ABSTRACT: We present a new ototoxicity grading system that has clearly defined and frequency-specific audiometric criteria. The purpose of this study was to validate this grading system by assessing its correspondence to audiology treatment recommendations and comparing it with the currently utilized Common Terminology Criteria for Adverse Events (CTCAE). A retrospective chart review was conducted using audiologic, demographic, and clinical data from 134 children receiving 149 courses of chemotherapy consisting of cisplatin and/or carboplatin. Pure-tone audiograms were evaluated using both our proposed grading criteria and the CTCAE criteria. The resulting grades were then compared with charted audiologic interventions and a number of clinical parameters to assess the clinical validity of the grading scale. Chang grade 2a or higher predicted audiologic intervention. Although both the Chang and CTCAE ototoxicity grades were significantly related to audiologist recommendations for assistive devices such as hearing aids and/or frequency modulated systems (P < .0001), the Chang scale was more specific, with the CTCAE scale diverging from clinical recommendation at higher grades. As expected, patients receiving cisplatin had more severe hearing loss with concurrent carboplatin administration, radiation therapy exposure, younger age, smaller body-surface area, longer treatment exposure, and more severe disease. This grading system provides robust and clinically useful criteria to represent clinical hearing loss induced by ototoxicity with regard to the impact on speech and language and the need for assistive hearing devices. It is both more specific and more sensitive than the traditional CTCAE criteria for identifying clinically significant ototoxicity.
    Journal of Clinical Oncology 03/2010; 28(10):1788-95. · 18.04 Impact Factor
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    ABSTRACT: An infant with a subglottic hemangioma remained in respiratory distress after multiple treatments failed and was found to have an enlarging mediastinal infantile hemangioma compressing the trachea. Treatment with oral propranolol resulted in resolution of symptoms within 2 days and a 50% reduction in lesion size within 1 week.
    The Journal of pediatrics 02/2010; 156(2):335-8. · 4.02 Impact Factor
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    ABSTRACT: To evaluate genotype-phenotype correlation over time for a cohort of children with connexin-26 (GJB2)-associated autosomal recessive hearing loss. Fifty-two children were identified from a database of individuals with homozygous or compound heterozygous mutations in GJB2 and subjected to chart review of their otolaryngologic and serial audiometric evaluations. Genotype-phenotype correlations were identified among the members of this group by appropriate statistical analyses. Hearing loss was most severe in individuals with two truncating mutations in GJB2 and mildest in those with two nontruncating mutations. Progressive hearing loss was seen directly by serial audiometry in 24% of all subjects, and suggested in a total of 28% when those with normal newborn hearing screens and subsequent hearing loss were included. Progression was particularly common among carriers of the p.V37I allele either in homozygosity or in compound heterozygosity with a truncating allele; these children are primarily of Asian descent and demonstrate mild, slowly progressive hearing loss. Phenotype in GJB2-associated hearing loss is correlated with genotype, with truncating mutations giving rise to more severe hearing loss. Progression of hearing loss is not uncommon, especially in association with the p.V37I allele. These results suggest that close audiometric follow-up is warranted for patients with GJB2-associated recessive hearing loss.
    Genetics in medicine: official journal of the American College of Medical Genetics 02/2010; 12(3):174-81. · 3.92 Impact Factor
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    ABSTRACT: The current study was conducted to determine whether 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. Patients who had stage I/II disease received treatment with 4 cycles of combined cisplatin, 5-fluorouracil, and vincristine (C5V) with or without amifostine. Patients who had stage III/IV disease were randomized to receive treatment with 6 cycles of either C5V with or without amifostine or carboplatin alternating with cisplatin (CC) with or without amifostine. Patients who were randomized to receive amifostine were given a dose of 740 mg/m2 intravenously over 15 minutes before 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 who received amifostine was similar to the outcome for patients who did not receive amifostine (P=.22). The incidence of significant hearing loss (>40 dB) was similar for patients who did or did not receive amifostine (38% [14 of 37 patients] vs 38% [17 of 45 patients], respectively; P=.68). 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=.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.
    Cancer 10/2009; 115(24):5828-35. · 5.20 Impact Factor
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    ABSTRACT: To compare the incidence of otorrhea in a group of infants with cleft palate (CP) and tympanostomy tubes before and after surgical repair of the CP. Prospective observational study. Otolaryngology clinic at a tertiary care children's hospital. Thirty-three infants with CP and middle ear effusions who underwent tympanostomy tube placement. Subjects were observed from the time of tube placement until 6 months after CP repair. Incidence of otorrhea before and after CP repair. Subjects were observed a mean of 6.3 months before CP repair and 6 months after CP repair. Before CP repair, 11 of 33 infants (33%) had no episodes of otorrhea, compared with 22 of 33 (67%) after CP repair (P = .007). Fourteen infants (43%) had 2 or more episodes of otorrhea before CP repair compared with 2 (6%) after CP repair (P = .001). Before CP repair, significantly fewer tubes were patent at the time of the audiologic evaluation compared with after CP repair (39 of 62 [63%] vs 52 of 66 [79%]; P = .048). Average speech reception threshold for the infants with tympanostomy tubes before CP repair was 18.1 dB compared with 12.6 dB after CP repair (P = .01). The incidence of otorrhea after tympanostomy tube placement before CP repair is higher than the incidence after CP repair, although more than half of all infants (19 [58%]) had either 1 or no episodes of otorrhea before CP repair.
    Archives of otolaryngology--head & neck surgery 09/2009; 135(8):748-51. · 1.92 Impact Factor
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    Kay W Chang, T J O-Lee, Melissa Price
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    ABSTRACT: Examination of neonatal hearing screening practices around the world suggests that more attention is placed on infants who fail bilaterally on their hearing screen than infants who refer (fail) in one ear. Some programmes only report bilateral failures as positive hearing screens. This study investigates how limitations of the screening techniques demand continued audiologic evaluations in unilateral referrals. The study sample consisted of all infants born at a single academic paediatric hospital between February 1998 and February 2002. There were 16,007 infants screened using ALGO automated auditory brainstem response. Eighteen of the infants who failed the screen in one ear but passed in the other ear were found to have permanent hearing loss, and had their subsequent clinical course and audiologic management analysed. The final audiologic outcome after four years in both the pass and fail ear were examined. One group of unilateral referrals (n = 6) had obvious anatomic reasons for the ear failing the screen (canal atresia/stenosis). There were five patients in which the ear that passed the screen was later found on more extensive audiologic evaluation to have significant hearing loss. Review of recent literature was also completed to examine the methods by which unilateral screening referrals are commonly reported and whether or not this affected follow-up diagnostic evaluation. Infants who pass one ear and refer one ear on neonatal hearing screening still need to have thorough and prompt evaluations. In many cases, the ear that passed can be found to have significant hearing loss.
    Journal of Medical Screening 02/2009; 16(1):17-21. · 2.35 Impact Factor

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