Brian W. Blakley

Strategies to advance translational research into brain barriers

There is a paucity of therapies for most neurological disorders--from rare lysosomal storage diseases to major public health concerns such as stroke and Alzheimers disease. Advances in the targeting of drugs to the CNS are essential for the future success of neurotherapeutics; however, the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by the blood-brain barrier, the blood-CSF barrier, or other specialised CNS barriers. These brain barriers are now recognised as a major obstacle to the treatment of most brain disorders. The challenge to deliver therapies to the CNS is formidable, and the solution will require concerted international efforts among academia, government, and industry. At a recent meeting of expert panels, essential and high-priority recommendations to propel brain barrier research forward in six topical areas were developed and these recommendations are presented here.

Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale

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, audiologists, 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.

Update on Intratympanic Gentamicin for Meniere's Disease†

Objective: To review the literature relating to intratympanic gentamicin injection therapy for Menieres disease to detect consistencies and differences that might suggest optimal technique.

Clinical Practice Guideline Tinnitus

Objective Tinnitus is the perception of sound without an external source. More than 50 million people in the United States have reported experiencing tinnitus, resulting in an estimated prevalence of 10% to 15% in adults. Despite the high prevalence of tinnitus and its potential significant effect on quality of life, there are no evidence-based, multidisciplinary clinical practice guidelines to assist clinicians with management. The focus of this guideline is on tinnitus that is both bothersome and persistent (lasting 6 months or longer), which often negatively affects the patient’s quality of life. The target audience for the guideline is any clinician, including nonphysicians, involved in managing patients with tinnitus. The target patient population is limited to adults (18 years and older) with primary tinnitus that is persistent and bothersome. Purpose The purpose of this guideline is to provide evidence-based recommendations for clinicians managing patients with tinnitus. This guideline provides clinicians with a logical framework to improve patient care and mitigate the personal and social effects of persistent, bothersome tinnitus. It will discuss the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the effect of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers. Action Statements The development group made a strong recommendation that clinicians distinguish patients with bothersome tinnitus from patients with nonbothersome tinnitus. The development group made a strong recommendation against obtaining imaging studies of the head and neck in patients with tinnitus, specifically to evaluate tinnitus that does not localize to 1 ear, is nonpulsatile, and is not associated with focal neurologic abnormalities or an asymmetric hearing loss. The panel made the following recommendations: Clinicians should (a) perform a targeted history and physical examination at the initial evaluation of a patient with presumed primary tinnitus to identify conditions that if promptly identified and managed may relieve tinnitus; (b) obtain a prompt, comprehensive audiologic examination in patients with tinnitus that is unilateral, persistent (≥ 6 months), or associated with hearing difficulties; (c) distinguish patients with bothersome tinnitus of recent onset from those with persistent symptoms (≥ 6 months) to prioritize intervention and facilitate discussions about natural history and follow-up care; (d) educate patients with persistent, bothersome tinnitus about management strategies; (e) recommend a hearing aid evaluation for patients who have persistent, bothersome tinnitus associated with documented hearing loss; and (f) recommend cognitive behavioral therapy to patients with persistent, bothersome tinnitus. The panel recommended against (a) antidepressants, anticonvulsants, anxiolytics, or intratympanic medications for the routine treatment of patients with persistent, bothersome tinnitus; (b) Ginkgo biloba, melatonin, zinc, or other dietary supplements for treating patients with persistent, bothersome tinnitus; and (c) transcranial magnetic stimulation for the routine treatment of patients with persistent, bothersome tinnitus. The development group provided the following options: Clinicians may (a) obtain an initial comprehensive audiologic examination in patients who present with tinnitus (regardless of laterality, duration, or perceived hearing status); and (b) recommend sound therapy to patients with persistent, bothersome tinnitus. The development group provided no recommendation regarding the effect of acupuncture in patients with persistent, bothersome tinnitus.

Post-tonsillectomy bleeding: How much is too much?

Complication rates become important in discussions for informed surgical consent and for quality assurance purposes. In an attempt to quantify literature-based rates for post-tonsillectomy bleeding, a MEDLINE search was carried out. Of 4,610 papers 63 reported post-tonsillectomy bleeding rates. The weighted mean, standard deviation and 95% confidence intervals were calculated for those papers. The mean (4.5%) plus 2 standard deviations (9.4%) suggests a maximum “expected” sustained bleeding rate of 13.9%. In the literature, which should reflect optimum results, there were 3 reports of bleed rates in the 18-20% range. These data may be useful for quality assurance committees and individual clinicians.

Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001.

Objectives To summarize the findings relevant to otolaryngology from the annual meeting of the Blood–Brain Barrier Disruption Consortium in Gleneden Beach, Oregon, March 10, 2001.

Post—Tympanostomy Tube Otorrhea: A Meta-Analysis

INTRODUCTION: Post—tympanostomy tube otorrhea is the most common complication of tympanostomy tube placement. The incidence of this problem varies from 3.4% to 74%. Trials that study post—tympanostomy tube otorrhea may involve valid randomization “by patient” or “by ear.” In an attempt to define “best practice,” we conduct a meta-analysis to quantify the benefit of using topical prophylactic antibiotic drops in the postoperative period. We then compare our findings with previous results found in the literature. METHODS: We selected randomized studies for which antibiotic drops had been used for at least 48 hours after tympanostomy tube insertion. Nine studies, 3 “by ear” and 6 “by patient,” met our inclusion criteria. The odds ratio and 95% confidence intervals were calculated for each to conduct the meta-analysis. RESULTS: Overall, prophylaxis appears to be effective at reducing the incidence of post—tympanostomy tube otorrhea. The odds ratios for all studies were less than 1.0. However, none of the 3 “by ear” studies and only 3 of the 6 “by patient” studies were statistically significant. The mean odds ratio was 52%, suggesting that prophylaxis may reduce the incidence of post—tympanostomy tube otorrhea by half. CONCLUSION: This meta-analysis suggests that routine post—tympanostomy tube prophylaxis is beneficial, but this finding is dependent on selection criteria used. EBM rating: A-1a

Clinical practice guideline: tinnitus executive summary.

The American Academy of Otolaryngology—Head and Neck Surgery Foundation (AAO-HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Tinnitus. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 13 recommendations developed address the evaluation of patients with tinnitus, including selection and timing of diagnostic testing and specialty referral to identify potential underlying treatable pathology. It will then focus on the evaluation and treatment of patients with persistent primary tinnitus, with recommendations to guide the evaluation and measurement of the impact of tinnitus and to determine the most appropriate interventions to improve symptoms and quality of life for tinnitus sufferers.

The role of tonsillectomy in reducing recurrent pharyngitis: A systematic review

Objective: To determine the evidence for efficacy of tonsillectomy in reducing the incidence of recurrent pharyngitis. Data Sources: Literature databases consisting of PUBMED, SCOPUS, CINHAL AND OVID EMBASE including all languages. Review Methods: Literature search of database by 2 authors with structured criteria using an online database. Selected studies evaluated with meta-analysis. Results: In four randomized, controlled trials tonsillectomy was favored over medical therapy in reducing pharyngitis. The difference was statistically significant in only one study. Overall meta-analysis results were significant, indicating that tonsillectomy results in a reduction of about 43% in the incidence of pharyngitis. The number needed to treat with tonsillectomy to prevent one sore throat per month for the first year after surgery was 11 (95% CI; 7-23). Conclusion: Tonsillectomy reduces the incidence of recurrent pharyngitis to a modest degree.

Quantification of sodium thiosulphate protection on cisplatin-induced toxicities.

OBJECTIVE To quantify the amount of protection from cisplatin (CDDP)-induced mortality and toxicity provided by sodium thiosulphate (STS). DESIGN Prospective controlled animal study. SETTING Animal research facility. METHOD Nephrotoxicity, myelotoxicity, and auditory/neurotoxicity were studied in guinea pigs. Total CDDP doses of 15, 21, 25, 35, and 45 mg/kg were administered to animals in groups of five. In some groups, STS (8000 mg/kg) was given. Animals underwent bloodwork and auditory brainstem response (ABR) testing to estimate toxicity before and 1 month after treatment. MAIN OUTCOME MEASURES Blood urea nitrogen, creatinine, and white blood cell count were used to assess renal and myelotoxicity. Hearing was assessed with ABR thresholds to click stimuli. Survival was an overall measure of toxicity. RESULTS Forty guinea pigs in six treatment groups were studied. Animals given 21 mg/kg CDDP all died within 1 month and showed evidence of severe toxicity. Eighty percent of subjects treated with CDDP 15 mg/kg survived and showed evidence of nephrotoxicity and ototoxicity. Subjects treated with STS and CDDP showed survival comparable to the control group treated with CDDP 15 mg/kg. Under STS protection, CDDP was tolerated in doses three times the toxic dose without protection. Without STS, the maximum dose of CDDP tolerated for a month was 15 mg/kg. CONCLUSIONS STS protects against mortality owing to CDDP by reducing toxicity. Under STS protection, the maximum tolerated dose of CDDP is greatly increased in guinea pigs.