Gaetano Paludetti

Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) content was determined by a radioligand receptor assay in 140 primary laryngeal squamous cell carcinomas (median value of 8.4 fmol mg-1 protein, range 0-169.9 fmol mg-1 protein). Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels are directly associated with the risk of death (chi 2 = 14.56, P-value = 0.0001) and relapse (chi 2 = 7.77, P-value = 0.0053). A significant relationship between EGFR status and survival was observed at the different arbitrary cut-off values chosen (8, 16 and 20 fmol mg-1 protein). The cut-off value of 20 fmol mg-1 protein was the best prognostic discriminator. In fact, the 5 year survival was 81% for patients with EGFR- tumours compared with 25% for patients with EGFR+ tumours (P < 0.0001). The 5 year relapse-free survival was 77% for patients with EGFR- tumours compared with 24% for patients with EGFR+ tumours (P < 0.010). When clinicopathological parameters and EGFR status were examined in the multivariate analysis, T classification and EGFR status retained an independent prognostic value. In this study we demonstrated that high EGFR levels single out patients with poor prognosis in laryngeal cancer.

Value of Fine-Needle Aspiration Cytology of Parotid Gland Masses

Objective To evaluate the usefulness and accuracy of fine‐needle aspiration cytology (FNAC) in the diagnosis of parotid gland masses.

Trafficking and Postsecretory Events Responsible for the Formation of Secreted Human Salivary Peptides A Proteomics Approach

To elucidate the localization of post-translational modifications of different classes of human salivary proteins and peptides (acidic and basic proline-rich proteins (PRPs), Histatins, Statherin, P-B peptide, and “S type” Cystatins) a comparative reversed phase HPLC-ESI-MS analysis on intact proteins of enriched granule preparations from parotid and submandibular glands as well as parotid, submandibular/sublingual (Sm/Sl), and whole saliva was performed. The main results of this study indicate the following. (i) Phosphorylation of all salivary peptides, sulfation of Histatin 1, proteolytic cleavages of acidic and precursor basic PRPs occur before granule storage. (ii) In agreement with previous studies, basic PRPs are secreted by the parotid gland only, whereas all isoforms of acidic PRPs (aPRPs) are secreted by both parotid and Sm/Sl glands. (iii) Phosphorylation levels of aPRPs, Histatin 1, and Statherin are higher in the parotid gland, whereas the extent of cleavage of aPRP is higher in Sm/Sl glands. (iv) O-Sulfation of tyrosines of Histatin 1 is a post-translational modification specific for the submandibular gland. (v) The concentration of Histatin 3, Histatin 5, and Histatin 6, but not Histatin 1, is higher in parotid saliva. (vi) Histatin 3 is submitted to the first proteolytic cleavage (generating Histatins 6 and 5) during granule maturation, and it occurs to the same relative extent in both glands. (vii) The proteolytic cleavages of Histatin 5 and 6, generating a cascade of Histatin 3 fragments, take place after granule secretion and are more extensive in parotid secretion. (viii) Basic PRPs are cleaved in the oral cavity by unknown peptidases, generating various small proline-rich peptides. (ix) C-terminal removal from Statherin is more extensive in parotid saliva. (x) P-B peptide is secreted by both glands, and its relative quantity is higher in submandibular/sublingual secretion. (xi) In agreement with previous studies, S type Cystatins are mainly the product of Sm/Sl glands.

Postlaryngectomy Pharyngocutaneous Fistula: Incidence, Predisposing Factors, and Therapy

OBJECTIVE: The pharyngocutaneous fistula (PCF) is a serious complication after total laryngectomy, and its etiology is not well understood yet. The aim of our study was to evaluate predisposing factors, incidence, and management of this complication. STUDY DESIGN AND SETTING: This was a retrospective study of 268 patients who underwent total laryngectomy in our clinic (January 1990-December 2001). A number of factors potentially predisposing to PCF formation were evaluated. RESULTS: A PCF was observed in 16% of patients. Systemic diseases, previous radiotherapy, supraglottic origin of tumor, and concurrent radical neck dissection were significantly associated with PCF. Spontaneous closure was noted in 28 patients, whereas a surgical closure was necessary in 15 patients. CONCLUSIONS: In presence of a specific risk factor, PCF can be expected; nevertheless, its prevention remains very difficult. Moreover, given the high percentage of spontaneous closure, we suggest the “wait and see” approach for 28 days before proceeding with a surgical approach.

Noise-Induced Hearing Loss (NIHL) as a Target of Oxidative Stress-Mediated Damage: Cochlear and Cortical Responses after an Increase in Antioxidant Defense

This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II–III and V–VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.

Pathogenesis of presbycusis in animal models: A review

Presbycusis is the most common cause of hearing loss in aged subjects, reducing individuals communicative skills. Age related hearing loss can be defined as a progressive, bilateral, symmetrical hearing loss due to age related degeneration and it can be considered a multifactorial complex disorder, with both environmental and genetic factors contributing to the aetiology of the disease. The decline in hearing sensitivity caused by ageing is related to the damage at different levels of the auditory system (central and peripheral). Histologically, the aged cochlea shows degeneration of the stria vascularis, the sensorineural epithelium, and neurons of the central auditory pathways. The mechanisms responsible for age-associated hearing loss are still incompletely characterized. This work aims to give a broad overview of the scientific findings related to presbycusis, focusing mainly on experimental studies in animal models.

In vivo protective effect of ferulic acid against noise-induced hearing loss in the guinea-pig

Ferulic acid (FA) is a phenolic compound whose neuroprotective activity was extensively studied in vitro. In this study, we provided functional in vivo evidence that FA limits noise-induced hearing loss. Guinea-pigs exposed to acoustic trauma for 1 h exhibited a significant impairment in auditory function; this injury was evident as early as 1 day from noise exposure and persisted over 21 days. Ferulic acid (150 mg/kg i.p. for 4 days) counteracted noise-induced hearing loss at days 1, 3, 7 and 21 from noise exposure. The improvement of auditory function by FA was paralleled by a significant reduction in oxidative stress, apoptosis and increase in hair cell viability in the organ of Corti. Interestingly in the guinea-pig cochleae, the neuroprotective effect of FA was functionally related not only to its scavenging ability in the peri-traumatic period but also to the up-regulation of the cytoprotective enzyme heme oxygenase-1 (HO-1); in fact, FA-induced improvement of auditory function was counteracted by the HO inhibitor zinc-protoporphyrin-IX and paralleled the time-course of HO-1 induction over 3-7 days. These results confirm the antioxidant properties of FA as free-radical scavenger and suggest a role of HO-1 as an additional mediator against noise-induced ototoxicity.

Epidermal growth factor receptor expression in primary laryngeal cancer: An independent prognostic factor of neck node relapse

Specimens of laryngeal squamous cell carcinoma (LSCC) were examined for epidermal growth factor receptor (EGFR) content using a radioreceptor method; 140 untreated consecutive patients with primary LSCC undergoing initial surgical resection were followed up for a median of 49 months (range 2–84 months) after surgery. Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels were directly associated with the risk of lymph node metastasis. A significant relationship between EGFR status and cervical node metastasis was observed. The cutoff value of 20 fmol/mg protein was the best prognostic discriminator. The 5‐year metastasis‐free survival (MFS) was 66% for patients with EGFR− tumors compared with 15% for patients with EGFR+ tumors. By multivariate analysis, the EGFR status appeared to be a significant independent prognostic factor for MFS. Our results suggest that the assessment of EGFR status at the time of diagnosis may identify a subset of LSCC patients highly susceptible to neck node metastases thus defining therapy accordingly. Int. J. Cancer (Pred. Oncol.) 84:188–191, 1999.

Long-term outcome of functional post-thyroidectomy voice and swallowing symptoms.

BACKGROUND Voice and swallowing symptoms are frequently reported early after thyroidectomy even in the absence of laryngeal nerves injury. We evaluated the short-term and long-term outcomes of these functional alterations. METHODS Consenting patients undergoing total thyroidectomy (TT) were enrolled. Videolaryngostroboscopy (VSL), acoustic voice analysis (AVA), and maximum phonation time (MPT) were performed pre-operatively, 3 months postoperatively, and >1 year postoperatively. Subjective evaluation of voice (Voice Impairment Score=VIS) and swallowing (Swallowing Impairment Score=SIS) were obtained pre-operatively, as well as 1 week, 1 month, 3 months, and >1 year postoperatively. RESULTS The long-term evaluation was completed in 110 patients. The percentage of patients with symptoms 1 week after operation was significantly higher than preoperatively, whereas it was significantly lower at long-term evaluation. VIS was significantly worse than pre-operatively, 1 week, 1 month, and 3 months after surgery, but it was similar to pre-operative >1 year after TT. SIS was significantly worse 1 week after thyroidectomy but not 1 month and 3 months after thyroidectomy, and it was significantly lower than the pre-operative >1 year after TT. CONCLUSION Vocal and swallowing symptoms are frequent after TT. In the absence of laryngeal nerve injury, after an initial impairment, late after operation, patients experienced subjective amelioration of their voice and swallowing performances, which may be related to the resolution of compressive symptoms.

Cisplatin ototoxicity in the guinea pig: vestibular and cochlear damage.

The aim of the present study was to investigate both vestibular and cochlear cisplatin toxicity. Twelve albino guinea pigs were divided into an experimental (n=8) and a control saline group (n=4) and were treated with cisplatin at a daily dose of 2.5 mg/kg for 6 consecutive days. Vestibular dysfunction was evaluated by computing the gain of the vestibular ocular reflex (VOR) evoked by stimulation in the horizontal (HVOR) and vertical (VVOR) planes. Changes in cochlear function were characterised as compound action potential threshold shifts. After the functional testing, tympanic bullae were removed and processed for morphological examination of the sensorineural epithelium. The onset of vestibular functional impairment was observed on the third day, although the VOR gain decrease was not significant. The impairment of the vestibular function progressed until the sixth day becoming statistically significant particularly at VVOR mid frequencies of stimulation. At these frequencies both macula and crista ampullaris functions are involved. Concomitantly a progressive auditory threshold shift was observed at all stimulus frequencies. The decline of the auditory function was statistically significant from the third day of treatment and it was more evident at high frequencies. Morphological observations showed a massive loss of outer hair cells and a degeneration of the organ of Corti in the basal/middle turns and only a slight loss of hair cells of the cristae ampullares and maculae. In conclusion, functional and morphological data provide evidence that the toxic effect of cisplatin is more pronounced in the organ of Corti than in the vestibular epithelium.