Audiological Monitoring in Children Treated with Platinum Chemotherapy.

Platinum compounds constitute the standard treatment for solid tumors in pediatric oncology. The purpose of this study is to assess the impact of platinum compounds in the development of ototoxicity in children following chemotherapy. This study included 160 patients treated with cisplatin and carboplatin for malignant solid diseases from 2007 to 2014. Their audiograms were classified according to the Boston SIOP ototoxicity scale. Twenty-five percent of the children treated with platinum compounds developed ototoxicity. The incidence of ototoxicity was correlated with the type of platinum derivative (i.e. cisplatin vs. carboplatin), coadministration of both drugs and concomitant cranial radiotherapy, but not with sex and age. Cumulative dose was correlated only with the cisplatin administration. Nine patients (8.6%) showed further progression of hearing impairment after the end of chemotherapy. The low rate of ototoxicity suggests the pivotal role of auditory monitoring in children treated with platinum compounds in order to be able to identify hearing loss at an early stage and to provide, jointly with pediatric oncologists, strategies to reduce further progression of cochlear toxicity.

Molecular targets for anticancer redox chemotherapy and cisplatin-induced ototoxicity: the role of curcumin on pSTAT3 and Nrf-2 signalling.

BACKGROUND: In oncology, an emerging paradigm emphasises molecularly targeted approaches for cancer prevention and therapy and the use of adjuvant chemotherapeutics to overcome cisplatin limitations. Owing to their safe use, some polyphenols, such as curcumin, modulate important pathways or molecular targets in cancers. This paper focuses on curcumin as an adjuvant molecule to cisplatin by analysing its potential implications on the molecular targets, signal transducer and activator of transcription 3 (STAT3) and NF-E2 p45-related factor 2 (Nrf-2), in tumour progression and cisplatin resistance in vitro and the adverse effect ototoxicity in vivo. METHODS: The effects of curcumin and/or cisplatin treatment have been evaluated in head and neck squamous cell carcinoma as well as in a rat model of cisplatin-induced ototoxicity by using immunofluorescence, western blot, and functional and morphological analysis. RESULTS: This study demonstrates that curcumin attenuates all stages of tumour progression (survival, proliferation) and, by targeting pSTAT3 and Nrf-2 signalling pathways, provides chemosensitisation to cisplatin in vitro and protection from its ototoxic adverse effects in vivo. CONCLUSIONS: These results indicate that curcumin can be used as an efficient adjuvant to cisplatin cancer therapy. This treatment strategy in head and neck cancer could mediate cisplatin chemoresistance by modulating therapeutic targets (STAT3 and Nrf2) and, at the same time, reduce cisplatin-related ototoxic adverse effects.

ENT function in a 14-days guinness scuba dive.

Scuba diving is known to affect the rhino-pharyngo-tubaric district (RPT unit). The aim of the study was to document function modifications of the RPT unit in 6 Italian divers (3 men and 3 women) who lived for 14 days consecutively at a depth of 8-10 m, breathing air (21% oxygen) at a pressure ranging between 1.8 and 2 ATA. RPT and inner ear assessment were carried out before the dive (TIME 0) and 24 h (TIME 1) after resurfacing, in order to investigate diving-related RPT and inner ear alterations. Physical examination after resurfacing revealed: fungal external otitis, otoscopic findings consistent with middle ear barotraumas and rhinosinusitis. Rhino-manometry showed a remarkable increase in inspiratory nasal flow and a substantial decrease in nasal resistance. No epithelial cell disruption was retrieved comparing pre and post resurfacing samples. Post-diving tubaric dysfunction was found. Pure tone audiometry revealed a bilateral 40 dB HL hearing loss at 4 kHz in 1 diver. Relevant PTA functions did not seem to be affected by the experiment, no remarkable changes were found at the Sensory Organisation Test and at the Motor Control Test. The 14-day underwater period had a positive effect on nasal flows and resistances.

Predictive role of audiological and clinical features for functional results after stapedotomy.

OBJECTIVE: To analyze and compare the preoperative factors that potentially influence the outcome of stapedotomy in our study group. MATERIALS AND METHODS: 161 cases were enrolled. Clinical variables considered to influence functional results - air conduction (AC) and bone conduction (BC) pure-tone average (PTA), air-bone gaps (ABG), sensorineural hearing loss (SNHL), ABG gain and DeltaSNHL - were gender, age, case type (unilateral vs. bilateral), ear side (right vs. left), pregnancy, vascular disease and family history of otosclerosis. The audiometric variables were preoperative AC- and BC-PTA, SNHL and ABG. RESULTS: Univariate logistic regression analysis showed that the probability of obtaining a > or =10 dB gain is significantly affected by the following factors: age <50 years, AC-PTA > or =50 dB and preoperative ABG > or =30 dB. All the other factors included into the registration (gender, familiarity, side, bilateral vs. unilateral, pregnancy, vascular diseases and preoperative BC-PTA) were not found to significantly affect postoperative gain (p > 0.05). Nevertheless, multivariate logistic regression analysis maintained a statistically significant correlation only between gain > or =10 dB and both preoperative ABG > or =30 dB and age <50 years. CONCLUSIONS: The accurate knowledge of predictive factors is a valuable tool that permits the surgeon to plan surgery with a better case selection as well as assisting in counseling the patient with regard to the likelihood of success of the procedure.

Protective effects of N-acetylcysteine on noise-induced hearing loss in guinea pigs.

Increasing evidence suggests the involvement of oxidative stress in noise-induced hearing loss. The present study analysed, in an animal experimental model, the time course of the pathogenic mechanisms of noise-induced cochlear damage and the efficacy of the antioxidant drug N-acetylcysteine in reducing noise ototoxicity. Animals were divided into two groups, exposed to noise one treated with N-acetylcysteine for 3 days and one (the control group) with saline. Acoustic trauma was induced by a continuous pure tone of 6 kHz, at 120 dB SPL for 30 minutes. Electrocochleographic recordings were made from an implanted round window electrode and the compound action potentials were measured daily at 2-16 kHz for 7 days. Morphological changes were analysed by scanning electron microscopy. The acoustic threshold measured 1 hour after acoustic trauma was elevated in the control group to 70-90 dB in the higher frequencies of the compound action potential audiogram, with a maximum threshold elevation ranging between 12 and 16 kHz. During the first 24 h, following acoustic trauma, there was a partial recovery of compound action potential thresholds of about 20 dB to reach a final threshold elevation of about 50-70 dB; there was no further improvement over the remaining experimental week. Animals treated with N-acetylcysteine showed a similar temporary threshold shift but a clear improvement in the recovery of compound action potential thresholds, with significantly reduced permanent threshold shift and hair cell loss. These data suggest that N-acetylcysteine is able to attenuate the toxic effect of acoustic trauma and could represent an interesting molecule for preventing inner ear injuries.

Ex vivo-transduced autologous skin fibroblasts expressing human Lim mineralization protein-3 efficiently form new bone in animal models.

Local gene transfer of the human Lim mineralization protein (LMP), a novel intracellular positive regulator of the osteoblast differentiation program, can induce efficient bone formation in rodents. To develop a clinically relevant gene therapy approach to facilitate bone healing, we have used primary dermal fibroblasts transduced ex vivo with Ad.LMP-3 and seeded on a hydroxyapatite/collagen matrix prior to autologous implantation. Here, we demonstrate that genetically modified autologous dermal fibroblasts expressing Ad.LMP-3 are able to induce ectopic bone formation following implantation of the matrix into mouse triceps and paravertebral muscles. Moreover, implantation of the Ad.LMP-3-modified dermal fibroblasts into a rat mandibular bone critical size defect model results in efficient healing, as determined by X-rays, histology and three-dimensional microcomputed tomography (3DmuCT). These results demonstrate the effectiveness of the non-secreted intracellular osteogenic factor LMP-3 in inducing bone formation in vivo. Moreover, the utilization of autologous dermal fibroblasts implanted on a biomaterial represents a promising approach for possible future clinical applications aimed at inducing new bone formation.

Giant deep lobe parotid gland pleomorphic adenoma involving the parapharyngeal space. Report of three cases and review of the diagnostic and therapeutic approaches.

Aim of the present report is to discuss and underline the diagnostic algorithm and the surgical approach to giant parotid pleomorphic adenomas arising in the deep lobe and growing in the parapharyngeal space. Three cases are described and a review is made of the international literature concerning giant deep lobe parotid gland pleomorphic adenoma. Diagnosis was based on imaging, computed tomography scan and magnetic resonance imaging and upon cytology, by means of fine needle aspiration biopsy. The surgical approach varied according to the location of the tumour. All patients were discharged without complications and no cases of permanent facial nerve palsy were observed. An exhaustive pre-operative diagnostic algorithm is required before approaching this lesion. Fine needle aspiration biopsy is, in our opinion, mandatory to avoid histological surprises. The surgical approach should provide excellent visibility with wide surgical exposure to secure local neurovascular structures.

Vascular endothelial growth factor (VEGF) expression in noise-induced hearing loss.

Noise-induced hearing loss has been associated with alterations in cochlear blood flow. Our study analyzed the expression of Vascular Endothelial Growth Factor (VEGF) and its functional receptors, Flt-1 and Flk-1, in the cochlear structures of noise-exposed and unexposed guinea pigs. VEGF is a prototypical angiogenic agent, with multiple functions on vascular biology, ranging from vascular permeability to endothelial cell migration, proliferation, differentiation, and survival. Acoustic trauma was induced by a continuous pure tone of 6 kHz, at 120 dB SPL for 30 min. Auditory function was evaluated by electrocochleographic recordings at 2-20 kHz for 7 days. Noise-induced cochlear morphological changes were studied by immunohistochemistry and scanning electron microscopy. The expression of VEGF and its receptors was examined by immunohistochemistry and western blotting analysis. The hearing threshold shift reached a level of 60 dB SPL on day 1 after trauma and underwent a partial recovery over time, reaching a value of about 20 dB SPL on day 7. Outer hair cell loss was more prominent in the area located 14-16 mm from the apex. Increased cochlear VEGF expression was observed in noise-exposed animals, in particular at the level of stria vascularis, spiral ligament, and spiral ganglion cells. No changes were observed in the expression of VEGF-receptors. Our data suggest a role for VEGF in the regulation of the vascular network in the inner ear after acoustic trauma and during auditory recovery, with potentially important clinical and therapeutic implications.

Protective effects of alpha-tocopherol and tiopronin against cisplatin-induced ototoxicity.

OBJECTIVE: To investigate the possible protective effects of alpha-tocopherol and tiopronin against cisplatin-induced cochlear damage. Cisplatin ototoxicity and nephrotoxicity seem to result from the inhibition of cochlear antioxidant defences, causing an increase in the amount of reactive oxygen species. Antioxidants, such as alpha-tocopherol and tiopronin, are able to suppress lipid peroxidation, thus attenuating tissue damage. MATERIAL AND METHODS: Hartley albino guinea pigs were used. The animals were treated for 7 consecutive days with either (I) cisplatin alone, (II) cisplatin+alpha-tocopherol acetate, (III) cisplatin+tiopronin, (IV) cisplatin+alpha-tocopherol acetate+tiopronin, (V) alpha-tocopherol acetate alone or (VI) tiopronin alone. Changes in cochlear function were characterized by means of compound action potential threshold shifts. After the functional testing, tympanic bullae were removed and processed for morphological examination of the sensorineural epithelium. Renal function was evaluated by measuring serum blood urea nitrogen and creatinine levels. RESULTS: Cisplatin induced progressive high-frequency hearing loss of 40-50 dB SPL. Alpha-tocopherol and tiopronin co-therapy significantly slowed the progression of hearing loss. Treatment with alpha-tocopherol acetate or tiopronin alone was less effective. Morphological observations showed an important loss of outer hair cells and degeneration of the organ of Corti in the basal and middle turns. Injection of both alpha-tocopherol and tiopronin reduced cochlear outer hair cell loss more than treatment with a single drug. Beneficial effects of alpha-tocopherol and tiopronin on cisplatin-induced nephrotoxicity were observed. CONCLUSION: This study supports the hypothesis that alpha-tocopherol and tiopronin interfere with cisplatin-induced damage, and suggests that concurrent treatment with the two drugs can be useful in protecting against hearing loss.

The role of antioxidants in protection from ototoxic drugs.

A number of studies have shown that cisplatin and gentamicin ototoxic effects may result from free radical-mediated damage due to the reduction of antioxidant substances and an increased lipid peroxidation. The authors summarize the results obtained evaluating the auditory and vestibular functions and the inner ear hair cell morphology and survival after administration of antioxidant agents against cisplatin and gentamicin. In the first experiment, albino guinea pigs were treated with gentamicin (100 mg/kg per day, i.m.) alone or gentamicin (100 mg/kg per day, i.m.) plus alpha-tocopherol (100 mg/kg per day, i.m.) for 2 weeks. In a second experiment, albino guinea pigs were injected with cisplatin (2.5 mg/kg per day) or cisplatin (2.5 mg/kg per day) plus tiopronin (300 mg/kg) for 6 days. Electrocochleographic recordings were made from an implanted round window electrode. In all experiments compound action potentials (CAPs) were measured at 2-16 kHz. Changes in cochlear function were characterized as CAP threshold shifts. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VOR). Frequency stimulation parameters ranged from 0.02 to 0.4 Hz and peak-to-peak amplitude was 20 degrees. Morphological changes were analysed by light microscopy and scanning electron microscopy. Both hearing loss and vestibular dysfunction induced by gentamicin were significantly attenuated by alpha-tocopherol. However, tiopronin co-therapy slowed the progression of hearing loss in cisplatin-treated animals and significantly attenuated the final threshold shifts. Cisplatin had little effect on the hair cells of cristae ampullares and maculae. Vestibular function was completely preserved in tiopronin co-treated animals. In conclusion, antioxidants such as alpha-tocopherol or tiopronin interfere with gentamicin and cisplatin damage and this suggests that they may be useful in preventing oto-vestibulotoxicity. Therefore, it is important to develop protective strategies that permit the avoidance of the toxic side effects of these drugs without interfering with their therapeutic effects.

Local application of sodium thiosulfate prevents cisplatin-induced hearing loss in the guinea pig.

Cisplatin (CDDP), an anticancer drug used extensively to treat a broad range of neoplasms, has strong ototoxic side effects. Sodium thiosulfate (STS) has been described as a protective agent against CDDP toxicity, but it also reduces CDDP's antitumoral cytotoxicity. To maintain the antitumoral effectiveness of systemic administration of CDDP, a strategy has been developed to apply STS directly into the cochlea. Perfusion of STS into the cochleae of guinea pigs completely prevented CDDP-induced hearing loss, with no change in either compound action potential (CAP) or distortion product otoacoustic emission (DPOAE) audiograms during the time course of the treatment. Histological analysis revealed a minimal loss of outer hair cells (OHCs) in the organ of Corti and no damage to the marginal cells of the stria vascularis as seen in animals exposed to CDDP. Cytocochleograms prepared 6 days after CDDP exposure showed that STS treatment protected more than 92.8% of OHCs and IHCs destined to die. Furthermore, it prevented CDDP-induced mitochondrial damage and subsequent translocation of cytochrome c, DNA fragmentation, and suppressed the apoptotic and necrotic hair cell degeneration. These results suggest that local application of STS may be an interesting strategy to prevent CDDP ototoxicity in patients undergoing CDDP chemotherapy.

Can chronic nasal obstruction cause dysfunction of the paratubal muscles and otitis media? An experimental study in developing Wistar rats.

OBJECTIVE: To quantitatively analyze modifications of the paratubal muscles in developing Wistar rats following nasal obstruction. MATERIAL AND METHODS: Twenty-four Wistar rats were used. Twelve were examined at 6, 8 and 12 weeks after birth and were considered normal controls. The nostrils of the remaining 12 rats were bilaterally obstructed by means of a synthetic resin 28 days after birth. The animals were sacrificed at either 2, 4 or 8 weeks after nostril occlusion. Serial sections were made in the dorsoventral plane and stained with hematoxylin-eosin. Four 5 x 5 microm2 areas, selected within the paratubal muscles, were histologically analyzed and the number of muscular fibers was counted manually. RESULTS: The number of tensor veli palatini muscle fibers progressively decreased in the obstructed rats compared with age-matched normal controls and in those that had been obstructed for 4 and 8 weeks these reductions were statistically significant. CONCLUSION: The correct development of the paratubal muscles seems to be linked to physiological nasal breathing and is negatively affected by oral breathing.

Auditory brainstem and cochlear implants: functional results obtained after one year of rehabilitation.

Very little information has been published on the clinical outcome of auditory brainstem implants (ABI). The present paper evaluates results obtained in a patient affected by a bilateral acoustic neuroma in type II neurofibromatosis who received an implant during removal of the residual tumor. One year later surgical revision of the ABI was necessary because no auditory sensation was obtained after ABI activation. Twelve months after the surgical revision, 12 electrodes out of 15 evoked auditory sensation. The results of rehabilitation were compared with those obtained in a group of eight postlingually deaf patients with cochlear implants (CI). Twelve months postoperatively the CI patients identified 97.7 +/- 5.1% of bisyllabic words in a closed set while the ABI patient identified 86%. CI patients recognized 87.1 +/- 11.3% of sentences and 81.3 +/- 14.8% of words with contextual cues while the ABI patient recognized 75% and 65% respectively. Speech recognition improved more slowly in the ABI patient than in the CI patients and his scores for open-set words and sentences without lip reading and contextual cues were poorer. Although the results obtained in the ABI patient were not as good as those obtained in the CI patients, the ABI patient said his quality of life was improved.