Novel connexin 30 and connexin 26 mutational spectrum in patients with progressive sensorineural hearing loss.

OBJECTIVE: Mutations in the gap junction protein beta-2 gene ('GJB2') are known to be responsible for mild to profound congenital and late-onset hearing loss. This study aimed to investigate the molecular basis of progressive hearing loss compared with non-progressive hearing loss. METHODS: Following clinical otorhinolaryngological evaluation, a genetic analysis was performed in a cohort of 72 patients with progressive sensorineural hearing loss. RESULTS: Pathological genotypes were established in 16 patients (22.2 per cent). Six different gap junction protein beta-2 gene mutations were detected in 15 patients, with the c.35delG mutation responsible for 56 per cent of the mutated alleles. A novel gap junction protein beta-6 gene ('GJB6') mutation (p.Met203Val) was observed in one patient with mild progressive hearing loss. CONCLUSION: Analyses of gap junction protein beta-2 and -6 genes revealed that similar pathological genotypes, occurring with similar frequencies, were responsible for progressive hearing loss, compared with reported genotypes for non-progressive hearing loss patients. Thus, genotype cannot be used to differentiate non-progressive from progressive hearing loss cases; in this study, patients both with and without an established pathological genotype had a similar clinical course.

Salivary gland tumours as second neoplasms: two cases and literature review.

OBJECTIVES: Patients who survive malignant tumours have an increased risk of second neoplasms, including those of the salivary glands. Mucoepidermoid carcinoma of the parotid gland is by far the most common type of second salivary gland tumour; other types have rarely been reported. We describe here two patients with a second tumour of the salivary glands. CASE REPORTS: The first patient was a 22-year-old woman with a low grade mucoepidermoid carcinoma of the parotid gland, which developed 21 years after completion of chemoradiotherapy for acute lymphoblastic leukaemia. The second patient was a 40-year-old woman with an epithelial-myoepithelial carcinoma of the buccal mucosa, which arose 11 years after treatment for two malignant neoplasms - retroperitoneal liposarcoma and squamous cell carcinoma of the uterine cervix. CONCLUSIONS: It is mandatory that survivors of cancer should be monitored carefully, so that the complications related to their previous disease and therapy are detected early and managed properly.

Inoperable oropharyngeal carcinoma treated with concomitant irradiation, mitomycin C and bleomycin - long term results.

Patients with inoperable head and neck tumors were treated concomitantly with radiochemotherapy with mitomycin C and bleomycin in our prospective randomized clinical trial (1991- 1993). For the subgroup of patients with oropharyngeal carcinoma the results with radiochemotherapy were significantly superior to irradiation alone. Such scheme of treatment was then adopted as standard method. Here we present the long-term results and dose- response relationships in patients with inoperable oropharyngeal carcinoma treated by the same radiochemotherapy scheme till 1997. Ninety-five patients with stage III and IV inoperable oropharyngeal squamous cell carcinoma were treated with curative intent, concomitantly with supra-voltage irradiation 2 Gy/day 5 times weekly to 60-73 Gy, bleomycin 5 mg 2 times weekly and. one application of mitomycin C 15 mg/m(2) after 10 Gy. Logistic dose- response curve was calculated. Median follow-up was 85 months. The loco-regional control, disease- free survival and overall survival at 5 years were 55%, 51% and 32% (95% CI: 44-67%, 41-62%, 22-42%), respectively. The probability of new primary malignancy at 5 years was 23%. In multivariate analysis performance status, biological equivalent dose, dose of bleomycin, and stage were identified as independent prognostic factors for loco-regional control, disease-free, and overall survival. Th gamma-value of dose response curve was 2.86. The outcome of the disease was directly proportional to intensity of irradiation and chemotherapy. It appears that in our concomitant radiochemotherapy MiC increased radioresponsiveness of the tumor by its effect on hypoxic fraction.

Impairments of vestibular system in infants at risk of early brain damage.

Children with early brain damage often present with balance disorders. We evaluated the vestibular apparatus function in 110 infants at risk of brain lesions. Our study confirmed a statistically significant correlation between vestibular apparatus dysfunction and the degree of neurological risk. Early recognition of vestibular disorders preconditions adequate rehabilatation and supports the acquisition of motor skills.

Amyloidosis of the larynx.

Amyloidosis of the larynx is an uncommon disease and mainly a local occurrence. Hoarseness is the prevalent symptom. Surgical excision of the amyloid masses is the treatment of choice. In the present paper, the authors describe seven cases treated in the last twenty years.

Voice quality after radiation therapy for early glottic cancer.

OBJECTIVE: To evaluate the voices of irradiated patients with early glottic carcinoma and to compare these with the voices of healthy volunteers. DESIGN: Case-control study. SETTING: University Department of Otorhinolaryngology and Cervicofacial Surgery, University of Ljubljana, Ljubljana, Slovenia. SUBJECTS AND METHODS: The voice samples (sustained vowel) of 50 patients (44 men and 6 women) who had been irradiated for T1 (43 subjects) or T2 (7 subjects) glottic squamous carcinoma at least 1 year prior to the study were analyzed with the Multi-Dimensional Voice Program (Kay Elemetrics Corp, Lincoln Park, NJ) and compared with those of a normal group of 50 age- and sex-matched volunteers. Average fundamental frequency, jitter, shimmer, noise-to-harmonic ratio, and degree of voiceless elements were determined. In the irradiated group, videostroboscopy was performed. The patients assessed their voice fatigue. RESULTS: The irradiated subjects demonstrated significantly higher values for jitter, shimmer, and degree of voiceless elements than did the healthy volunteers. The values for noise-to-harmonic ratio were higher in the irradiated group, but the difference was not significant (P =.08). The values for fundamental frequency were almost equal in both groups. In most of the irradiated subjects, some irregularities of the vocal fold vibration were noticed. Many of these patients also reported voice fatigue. CONCLUSIONS: Radiation therapy for early glottic cancer results in poorer voice quality compared with normal age- and sex-matched speakers. In most of the irradiated patients, greater than normal effort in voice production was found based on patient assessment. This may result from stiffness of the vibratory source and inadequate compensatory maneuvers in phonation. We suggest that voice therapy during and after radiation therapy may result in better voice quality.

Autofluorescence imaging in the diagnosis of laryngeal cancer.

Differences in autofluorescence (fluorescence without photodynamic drugs) between normal and malignant tissues offer new possibilities in detecting and localizing early laryngeal carcinoma. Autofluorescence imaging was performed using a modified fluorescence endoscopy system from Xillix Technologies (Richmond, Canada). Fluorescence was induced by blue light at 442 nm and captured by an image-intensified camera through a laryngeal telescope. The images were then processed by the system and displayed on a video monitor. Normal tissue appeared green while malignant sites appeared reddish-brown. The autofluorescence imaging technique was compared to standard microlaryngoscopy in 108 patients with laryngeal pathologies (in 74 of whom malignancy was suspected). The acquired reflectance and fluorescence images of each lesion were assessed independently as malignant or not malignant by three ENT specialists who were familiar with the procedure but were not provided with clinical data or histopathological information concerning the lesion. The assessments of pathology were determined from the two imaging modalities and were compared to histopathological findings of the biopsy specimens taken from the lesion. The present study showed that autofluorescence imaging can be a useful complementary method to microlaryngoscopy for detecting and delineating laryngeal malignancies. If in the future, the device can be developed for use in an outpatient office, a significant improvement can be made for the early detection of laryngeal malignancies.

Pure tone audiogram and speech audiometry in patients with hereditary motor and sensory neuropathy.

The goal of our work was to determine hearing thresholds in patients with hearing impairment due to hereditary motor and sensory neuropathy (HMSN I). In assessment of auditory function we used two methods: pure tone and speech audiometry. Pure tone audiometry was performed using air and bone conducted signals. Speech comprehension was defined with a test battery of monosyllabic words unknown to the patient. By comparing the results of these methods we were able to differentiate whether the hearing loss was of cochlear or retrocochlear origin. We tested 5 patients with HMSN I associated with difficulty in speech understanding. The tests showed mild to severe elevation of pure tone thresholds but no speech perception in any of tested patients. We suggest that this type of hearing impairment be due to the disorder of the auditory nerve function--a neuropathy of the auditory nerve as part of HMSN.

Does it make sense to preserve the stapedial muscle during surgical treatment for otosclerosis?

Our study aimed to show whether it is useful to preserve the stapedial muscle during the surgical treatment of otosclerosis. The study was carried out on 67 patients with tympanoscopic evidence of otosclerosis. In group A (34 patients) the stapedial muscle was intra-operatively preserved as follows: the stapedial suprastructure with preserved muscle tendon was transpositioned onto the longer arm of the incus and secured with a wire loop. The mean uncomfortable level for sounds was measured after surgery and the results of group A patients were compared with those obtained in group B (33 patients, who underwent standard surgery). One month after surgery, in group A patients, the cochleostapedial reflex was evoked in 21 patients (61.8 per cent) and two months later in 32 patients (94.1 per cent). One month after operation, in group A patients the mean uncomfortable level was 108.8 dB, while three months later it increased to 114.1 dB. In group B, the relevant values were 97.8 dB one month after surgery, and 98.0 dB three months later. Our presumption that stapedial muscle preservation is necessary has been proved by the fact that the patients with the preserved muscle had a higher noise discomfort threshold.

Role of surface EMG in diagnostics and treatment of muscle tension dysphonia.

In muscle tension dysphonia (MTD) excessive tension of both the internal and external laryngeal muscles is observed. In the present pilot study, 9 pairs of surface electrodes were used to determine the electromyographic (EMG) characteristics of different muscles in the perioral area and anterior neck before and during phonation. Eleven patients with MTD and 5 normal speakers were included within the study. The results show a 6-8-fold increase of EMG activity and/or an alternation of the EMG activity level in the perioral and supralaryngeal muscles before and during phonation in most of the patients with MTD. It is not clear whether these muscles are activated as compensation for excessive tension of internal laryngeal muscles, or whether they are responsible for some of the voice disorders.

Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report.

PURPOSE: To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone. METHODS AND MATERIALS: Between March 1991 and December 1993, 64 patients with inoperable head and neck carcinoma (41 with oropharyngeal site) were randomized to radiotherapy alone (group A) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin (group B). In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66-70 Gy. The planned concomitant treatment in group B was: bleomycin 5 units twice a week i.m., total dose 70 units, mitomycin C 15 mg/m2 i.v. after delivery of 10 Gy, and 10 mg/m2 i.v. on the last day of radiotherapy. To enhance the effect of these two drugs, patients received also nicotinamide, chlorpromazine, and dicoumarol. Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma, the study was closed and such patients were after December 1993 routinely treated with the combined therapy (as in arm B). Until October 1996, we treated and followed up 48 such consecutive patients. RESULTS: Median follow-up of our study patients is 42 months. Complete remission (CR) rate in group A was 31% and in group B 59% (p = 0.04); disease-free survival (DFS) in group A was 8% and in group B 37% (P = 0.01); and overall survival (OS) was 7% in group A and 26% in group B (p = 0.08). CR rate for patients with oropharyngeal carcinoma was 29% in group A (N = 21) and 75% in group B (N = 20) (p = 0.007); DFS in group A was 10% and in group B 48% (p = 0.001); and the OS was 10% in group A and 38% in group B (p = 0.019). In patients with inoperable oropharyngeal carcinoma treated after December 1993, complete remission was achieved in 32/48 (67%, 95% CI: 52%-80%). DFS at the median follow-up of 14 months was 60% (95% CI 43-77%) and OS 58% (95% CI 42-74%). CONCLUSION: From the results of our study it seems that the concomitant treatment significantly improves CR rate, DFS, and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone.

Estimation of arterial CO2 partial pressure by measurement of tracheal CO2 during high-frequency jet ventilation in patients with a laryngectomy.

Tracheal and arterial CO2 partial pressures were measured simultaneously in 27 laryngectomized patients both while they were awake and during high-frequency jet ventilation. Tracheal gas was sampled during brief interruptions of high-frequency jet ventilation. Agreement between tracheal and arterial CO2 partial pressures was assessed using the Bland-Altman method. The tracheal-arterial CO2 partial pressures gradient during spontaneous breathing was significantly lower (P < 0.0002) than during high-frequency jet ventilation. During spontaneous ventilation, the bias was -0.77 kPa (95% CI = -0.99 to -0.55 kPa), and the upper and lower limits of agreement were 0.29 kPa (95% CI = -0.11 to -0.7 kPa) and -1.83 kPa (95% CI = -2.24 to -1.43 kPa). During high-frequency jet ventilation, the bias was -1.61 kPa (95% CI = -1.76 to -1.46 kPa), and the limits of agreement were -0.48 kPa (95% CI = -0.75 to -0.21 kPa) and -2.74 kPa (95% CI = -3.01 to -2.47 kPa). Despite the poor agreement between tracheal CO2 partial pressure and arterial CO2 partial pressure, it is sufficient to allow for adjustment of ventilator settings during jet ventilation.

Instability of voice in adolescence: pathologic condition or normal developmental variation?

OBJECTIVE: Pediatricians often send adolescents with dysphonia to the otorhinolaryngologist's office to find the reason for their hoarseness. The aim of this study was to identify the main characteristics of adolescent voice and to determine which characteristic (variable of voice analysis) can distinguish normal variations of voice development from pathologic disorders. STUDY DESIGN: On the basis of history, indirect laryngoscopy, and stroboscopy, 51 adolescents (22 boys, 29 girls) from age 10 to 17 years were divided into four subgroups: candidates for singing lessons without voice problems, subjects with mutation voice disorders, subjects with functional dysphonia, and subjects with vocal cord nodules. Voice analysis by Multi-Dimensional Voice Program (Kay Elemetrics) evaluated the fundamental frequency, the variability of pitch and amplitude (loudness), and the presence of noise in the analyzed voice sample of each of the subjects. Data were analyzed with the SPSS+/PC Statistical Program. RESULTS: All mean values of variables that describe variability of pitch and amplitude were abnormal in boys and in girls, with greater abnormality among boys. The variability of loudness and specifically the variability of pitch were abnormal in a majority of subjects. A significant negative correlation between age and fundamental frequency was stated in boys only and between age and variability of amplitude in girls only. Variables that express variability of pitch and amplitude correlated positively between themselves. No significant differences were found between the first subgroup (candidates for singing lessons), which represented a normal population, and the other three subgroups (subjects with mutational disorders, functional dysphonia, and vocal cord nodules). In addition, no significant differences were found between the first three subgroups (subjects without voice problems and subjects with functional voice disorders) and the fourth subgroup (subjects with vocal cord nodules: organic lesion of laryngeal mucosa). CONCLUSIONS: According to this study, the main characteristic of adolescent voice is the instability of amplitude (loudness) and specifically the instability of pitch. Female voices appear more stable than male voices. No single variable of performed voice analysis can distinguish normal variation of voice development from pathologic disorders. The reason for this instability can be attributed to more gradual adaptation of the afferent and efferent nervous control to the rapid growth of the phonatory, respiratory, and resonatory organs. In the growing speech apparatus, optimal phonatory patterns can be created; therefore adolescence is an ideal period for treatment of functional voice disorders.

Detection and localization of early laryngeal cancer with laser-induced fluorescence: preliminary report.

Differences in autofluorescence between normal and malignant tissues offer new possibilities for detecting and localizing early laryngeal carcinomas. In the present study imaging was performed using a specially designed device that exploits differences in fluorescent properties of normal and cancerous tissues without photodynamic drugs. Fluorescence was induced by a helium-cadmium laser, captured by an image-intensified camera and displayed on a video monitor after previous computerization. Thirty patients were evaluated, of whom 18 had suspect malignancies. Laryngoscopic appearances during standard microlaryngoscopy were compared to fluorescence images, computerized fluorescence intensities and histopathological findings. The experience from this study shows that autofluorescence laryngoscopy may be a useful complementary method for detecting laryngeal malignancies.

Prognostic value of cathepsins B, D and steffins A and B in laryngeal carcinoma.

Concentrations of cathepsins A, D and stefins A and B were measured in primary tumor and adjacent normal tissue of 25 patients with laryngeal carcinoma. Median concentrations of both cathepsins and that of stefin B were significantly higher in tumor tissue than in their normal counterparts (cathepsins B and D, P < 0.0001; stefin B, P = 0.01), indicating their possible involvement in the process of tumor spread. Early (T1 and T2) tumors had lower concentrations of stefins A and B than locally advanced (T3 and T4) tumors (P = 0.04). Disease-free and disease-specific survival rates at 45 months were significantly better in patients with tumor concentrations of stefins above or equal to the cut-off values (stefin A, P = 0.001 and P = 0.004; stefin B, P = 0.048 and P = 0.008), indicating that these might be of prognostic value. The concentrations of cathepsins B and D did not correlate with survival.

Laser induced fluorescence in diagnostics of laryngeal cancer.

Differences in autofluorescence between normal and malignant tissues offer new possibilities for detecting and localizing early laryngeal carcinomas. In the present study imaging was performed using a specially designed device that exploits differences in fluorescent properties of normal and cancerous tissues without photodynamic drugs. Fluorescence was induced by helium-cadmium laser, captured by an image-intensified camera and displayed on a video monitor after previous computerization. 40 patients were evaluated, of whom 20 had suspect malignancies. Laryngoscopic appearances during standard microlaryngoscopy, fluorescence images and computerized fluorescence intensities were compared to histopathological findings. The experience from this study shows that autofluorescence laryngoscopy may be a useful complementary method for detecting laryngeal malignancies.

The role of allergy in the etiopathogenesis of laryngeal mucosal lesions.

The results of this study showed that allergy is an important factor in the etiopathogenesis of laryngeal mucosal lesions. Despite adequate treatment, no other unfavourable factors appeared to have significant influence on the results of the treatment. It seems that hypersensitivity to different inhalatory and nutritional allergens make laryngeal mucosa more susceptible for adverse action of other factors: vocal misuse, gastroesophageal reflux (GER), smoking, irritants in the surrounding microclimate, endocrinologic disorders, etc. Acting together, all these factors cause the development of laryngeal mucosal lesions. In the treatment of noninfectious laryngitis, vocal cord nodules, polyps or Reinke's edema, all the stated adverse factors should be identified and suitably diminished or eliminated. Allergy (Ig-E-mediated and non-IgE-mediated) should be considered as only one of the etiopathogenetic factors.

Prognostic value of cathepsins B, H, L, D and their endogenous inhibitors stefins A and B in head and neck carcinoma.

To estimate the prognostic value of cathepsins B, H, L, D and stefins A and B in head and neck carcinoma, their concentrations in cytosols of primary tumours and adjacent normal tissue were measured (cathepsins B, D stefins A, B in 45, cathepsin L in 24 and cathepsin H in 21 patients). Median concentrations of cathepsins B, L, and D were significantly higher in tumour than in the adjacent normal tissue (B and D: p < 0.0001; L: p = 0.004); cathepsin H concentration was higher in normal tissue (p = 0.001). Concentrations of either stefin did not differ significantly between normal and tumour tissue. Concentrations of cathepsins B, H, L, and D were higher in laryngeal than in non-laryngeal normal and tumour tissues. The difference was statistically significant for cathepsin B in tumour tissue (p = 0.045), and marginally significant in normal tissue (p = 0.07). Early tumours had lower concentrations of stefins A and B than locally advanced tumours (stefin A: p = 0.04; stefin B: p = 0.07). Disease-free and disease-specific survival rates were better in patients with concentrations of cathepsin L in tumour tissue below or equal to the cut-off values (p = 0.035; p = 0.05), whereas for cathepsin B the difference was established only for disease-free survival (p = 0.07). The opposite was true for stefin A (p = 0.0002; p = 0.002) and stefin B (p = 0.009; p = 0.003), and in disease-free survival also for cathepsin H (p = 0.055). The concentration of cathepsin D did not correlate with survival. Our data indicate that cathepsins B, H, L and stefins A and B might have prognostic value in head and neck carcinoma.

Radiotherapy, combined with simultaneous chemotherapy with mitomycin C and bleomycin for inoperable head and neck cancer--preliminary report.

PURPOSE: Prospectively designed randomized clinical study was undertaken to assess the efficacy of simultaneous application of irradiation, Mitomycin C, and Bleomycin in treatment of patients with inoperable head and neck carcinoma. METHODS AND MATERIALS: Between March 1991 and October 1993, 49 patients with inoperable head and neck carcinoma were randomly assigned to receive either radiation therapy alone (group A) or radiotherapy combined with simultaneous application of Mitomycin C and Bleomycin (group B). Patients in both groups were irradiated five times weekly with 2 Gy to the total dose of 66-70 Gy. Chemotherapy regimen included intramuscular application of Bleomycin 5 units twice a week, with the planned dose being 70 units and Mitomycin C 15 mg/m2 applied intravenously after delivery of 9-10 Gy of irradiation. The application of Mitomycin C was planned to be repeated on last day of radiotherapy in the dose of 10 mg/m2. In attempt to enhance the effect of chemotherapeutic drugs, patients in group B received also Nicotinamide, Chlorpromazine, and Dicoumarol. RESULTS: The difference in complete response rate between both treatment groups (24% in group A and 63% in group B) was statistically significant (p = 0.015). The difference in response rate was much more pronounced in patients with oropharyngeal carcinoma only (18% in group A compared to 81% in group B; p = 0.0003), while for all other subgroups added together, there was observed no benefit of multidrug therapy. Median follow-up was 18 months. Disease-free survival of patients in group A (9%) was significantly lower then in group B (48%) (p = 0.001). The difference between both treatment groups was even greater in patients with oropharyngeal carcinoma only: disease-free survival of these patients in group B was 66%, while in group A, all recurred (p = 0.00001). CONCLUSION: From results of our prospective randomized study it seems that the group of patients that received multidrug treatment with Mytomycin C, Bleomycin, Nicotinamide, Chlorpromazine, and Dicoumarol as enhancers of radiotherapy fared better than patients treated by radiotherapy alone.