Chemoradiation for locally advanced squamous cell carcinoma of the head and neck for organ preservation and palliation.

OBJECTIVES: To measure the efficacy and toxic effects of our chemoradiotherapy regimen by means of response and survival in patients with advanced squamous cell carcinoma of the head and neck (HNSCC) for organ preservation in resectable disease or palliation in unresectable disease. DESIGN: All patients underwent evaluation by the multidisciplinary head and neck cancer team, with pathological diagnosis and staging. All patients underwent assessment for response to therapy using results of physical examination and radiologic imaging. Patients were followed up at 3-month intervals for a planned period of 5 years. SETTING: Academic center. PATIENTS: Thirty-eight previously untreated patients with newly diagnosed HNSCC were treated from June 1, 1996, through December 31, 1998, of whom 20 had resectable and 18 had unresectable tumors. INTERVENTION: Patients received intravenous cisplatin, 100 mg/m(2) for 1 hour on days 1 and 29; a 24-hour continuous infusion of fluorouracil, 1000 mg/m(2) on days 1 through 4 and 29 through 32; and radiation therapy, 150 rad twice daily for 12 days. The patients were given a 7- to 10-day break, and radiation therapy was restarted on day 29 for 12 additional days (total dose, 7200 rad). MAIN OUTCOME MEASURES: Complete, partial, and total response rates; disease-free survival; overall survival; and toxic effects. RESULTS: Toxic effects of treatment were moderately severe, including grades III to IV mucositis (89%), neutropenia (71%), and renal toxic effects (8%). In the 18 patients in the unresectable group, complete response in the 17 primary tumors and 15 cervical nodal metastases was achieved in 12 (71%) and 9 (60%), respectively; in the 20 patients undergoing organ preservation, complete response rates were 100% in the 23 primary tumors and 15 cervical nodal metastases. Complete response for all 38 patients was achieved in 31 (82%). In the unresectable group, the Kaplan-Meier relapse-free survival estimate is 56%, with follow-up from 29 to 45 months. In the organ preservation group, 75% of patients are alive without disease, and 8 have been followed up for 36 to 48 months. Of the 5 patients who have died, only 2 died of disease, with recurrences at 13.0 and 16.5 months. CONCLUSIONS: Chemoradiotherapy consisting of cisplatin, fluorouracil, and twice-daily external beam radiation is highly effective in achieving durable complete responses in patients with resectable HNSCC undergoing organ preservation and patients with unresectable HNSCC undergoing palliation. Toxic effects of this regimen were moderate to severe.

Late-phase allergy and eustachian tube dysfunction.

OBJECTIVE: This study investigated the role of late-phase allergy in the development of otitis media with effusion. METHODS: Brown Norway rats were sensitized to ovalbumin and later challenged transtympanically. Eustachian tube ventilatory function was assessed 2, 4, 8, 24, 28, and 32 hours postchallenge by measuring passive opening and closing pressures, active clearance of positive and negative middle ear pressure, and mucociliary clearance. RESULTS: The results demonstrate that exposure to transtympanic allergen induces eustachian tube dysfunction and subsequent formation of effusion. Allergic animals showed significant increases in passive and active opening pressures, as well as a decreased ability to actively clear middle ear pressure. Finally, the mucociliary was significantly impaired in all sensitized rats exposed to transtympanic allergen. CONCLUSION: These findings demonstrate that late-phase allergy leads to significant eustachian tube dysfunction and subsequent formation of effusion by impairing the ventilatory and clearance functions of the eustachian tube.

Transient inflammation and dysfunction of the eustachian tube secondary to multiple exposures of simulated gastroesophageal refluxant.

Gastroesophageal reflux is a common problem in the newborn and preschool periods. Recent research suggests that it may be related to eustachian tube dysfunction and otitis media with effusion. The purpose of this experiment was to investigate the relationship between simulated gastroesophageal reflux and eustachian tube dysfunction. Rat middle ears were repeatedly exposed (transtympanically) to pepsin in hydrochloric acid or to phosphate-buffered saline solution. Their eustachian tube function was evaluated by assessing passive opening and passive closing pressures, and active clearance of positive and negative pressure. The passive pressure function tests showed variable results. The rats exposed to pepsin in hydrochloric acid had an impaired ability to clear positive and negative pressure from the middle ear as compared to the rats exposed only to phosphate-buffered saline solution. The results demonstrate that multiple middle ear exposures to pepsin in hydrochloric acid leads to eustachian tube dysfunction in rats.

Function of the eustachian tube after weekly exposure to pepsin/hydrochloric acid.

OBJECTIVE: To determine the effects of repeated pepsin/hydrochloric acid (HCl) exposure on the eustachian tube (ET). STUDY DESIGN AND SETTING: ET function was studied in 22 rats. Group I (control) rats received transtympanic phosphate buffered saline solution; groups II (0.5 mg/ml) and III (2.0 mg/ml) received transtympanic pepsin/HCl. Test solutions were applied on day 0 with ET function evaluated on days 1, 2, 3, and 7 after exposure. Each 7-day period represents 1 cycle; all groups underwent 4 cycles. ET function was evaluated using passive opening and closing pressure, and active clearance of positive and negative pressure tests. RESULTS: Rats exposed to pepsin/HCl had elevated passive opening pressures and a decreased ability to clear positive and negative pressure. A temporal relationship exists. CONCLUSION: The results suggest middle ear exposure to pepsin/HCl leads to ET dysfunction in rats, and that this dysfunction is enhanced with repeated exposures. SIGNIFICANCE: Gastroesophageal reflux may induce ET dysfunction.

Management of the carotid artery at the skull base.

PURPOSE: To determine appropriate management of benign lesions with significant involvement of the carotid artery at the skull base and present an algorithm for safe treatment of these patients. MATERIALS AND METHODS: From 1982 to 1999, 115 patients with significant parapharyngeal space masses were treated at our institution. Of these patients, 43 had lesions involving the carotid artery at the skull base and served as the basis for this study. All patients underwent preoperative computed tomography or magnetic resonance imaging scans to determine carotid involvement, and all had preoperative 4-vessel arteriograms and carotid occlusion tests with continuous electroencephalography or neurologic examination monitoring to predict safety of carotid sacrifice. RESULTS: Of 43 patients, 41 passed carotid occlusion testing and were treated surgically. Of these patients, 33 (81%) underwent resection of their lesions with preservation of the internal carotid artery, 5 (12%) had resection with bypass or reconstruction of the artery, and 3 (7%) had en bloc resections without artery reconstruction. There were no transient or permanent neurologic sequelae in any patient. CONCLUSIONS: When carotid artery encasement occurs in the setting of benign lesions at the skull base, safe resection with vascular preservation is possible in most cases. If carotid artery resection is necessary, vascular bypass or reconstruction is recommended to minimize neurologic morbidity.

Action of histamine on eustachian tube function.

INTRODUCTION: The role of allergy in eustachian tube dysfunction is controversial. In this study, allergy was simulated by exposure to histamine, and eustachian tube function testing was performed in an experimental rat model. METHODS: Ventilatory function was assessed by measuring passive opening and closing pressures of the eustachian tube after challenge with either transtympanic or intranasal histamine. The mucociliary clearance time of the tubotympanum was assessed by observing dye transport from the middle ear to the nasopharynx after challenge with either transtympanic histamine or control solution. RESULTS: There was a statistically significant increase in passive opening and closing pressures with transtympanic histamine versus intranasal histamine. In addition, mucociliary clearance times of the tubotympanum after transtympanic histamine showed a statistically significant increase when compared with those after transtympanic control solution. CONCLUSIONS: Transtympanic histamine exposure causes eustachian tube dysfunction in the rat by increasing passive opening and closing pressures of the eustachian tube and impairing mucociliary clearance time.

Allergy testing and immunotherapy in an academic otolaryngology practice: a 20-year review.

OBJECTIVE: Allergic disease plays a central role in the clinical practice of otolaryngology. The purpose of this study was to review the 20-year experience of an allergy clinic integrated within an otolaryngology practice at a major academic institution. STUDY DESIGN: We performed a retrospective database review of over 3300 otolaryngology patients referred for allergy skin testing between 1979 and 1999. RESULTS: Approximately 80% of patients referred for allergy testing in our clinic had positive test results, of which 75.7% went on to undergo desensitization. The most common allergen was house dust, with allergies to mites, ragweed, and grass also prevalent. Among current allergy immunotherapy patients, 30.8% have undergone nasal septal, turbinate, and/or endoscopic sinus procedures in addition to allergy management. Nasal obstruction was the symptom most frequently persistent despite immunotherapy and the one most frequently reported to be improved by surgery. CONCLUSIONS: The otolaryngologist-head and neck surgeon is uniquely qualified to perform comprehensive medical and surgical management for patients with complex disease processes involving a component of allergy. We believe that an integrated approach to allergy within an otolaryngology practice optimizes the treatment of such patients.

Cochlear implant performance in senior citizens.

Cochlear implants are indicated for elderly patients with severe-to-profound hearing loss (sensorineural hearing loss >/=70 dB). Their use has been limited, possibly by the misconception that elderly patients will perform poorly. To document the performance of older adults (> or =65 years old), we undertook a retrospective analysis of our postlingually deafened adult patients who underwent implantation with the CLARION Multi-Strategy Cochlear Implant and underwent formal audiologic analysis (sentence recognition [Central Institute for the Deaf, CID] and monosyllabic word recognition (consonant-noun-consonant, CNC)). Both younger (n = 20; mean age = 46.9 years) and older (n = 16; mean age = 71.5 years) adults showed statistically significant increases in CID and CNC scores after cochlear implantation. No statistically significant difference could be detected in operative time, anesthesia time, length of hospitalization, or CID or CNC scores between the two age groups. We conclude that age should not be a criterion for deciding who should receive cochlear implants.

An animal model for the study of genetic predisposition in the pathogenesis of middle ear inflammation.

OBJECTIVES: Chronic otitis media with effusion (COME) is the most prevalent inflammatory disease in children and is associated with numerous adverse long-term sequelae. Many factors have been associated with an increased risk of developing COME, one of which may be a genetic predisposition to the disease. To study the role that genetics play in the pathogenesis of COME, we used an animal model to compare the middle ear inflammatory responses in two different strains of rats (Lewis and Fisher). METHODS: In earlier studies, we demonstrated that exposure of the middle ear to endotoxin caused early extensive exudation and, later, goblet cell hyperplasia and mucin hypersecretion. In the present study, the animals were divided into six groups. In each group the animals were given transtympanic injection with gram-positive bacterial cell wall product (peptidoglycan-polysaccharide [PG-PS]). The middle ear bullae were studied at 1 week and 3 weeks after infection, and after systemic reinfection. Comparisons were made of the quantity of mucin exudate by enzyme-linked immunosorbent assay and by histological evaluation of the middle ear epithelial thickness. RESULTS: Our data demonstrate a statistically significant difference in middle ear inflammation and effusion formation between the two genetically different strains of rats. CONCLUSIONS: These data support the hypothesis that the middle ear response to PG-PS may be genetically determined and therefore suggest that genetic predisposition may play a role in the pathogenesis of COME.

The workforce in otolaryngology-head and neck surgery: moving into the next millennium.

OBJECTIVE: The goal was to examine the current scope of otolaryngologists' practices, their geographic distribution, and the roles otolaryngologists and other specialists play in caring for patients with otolaryngic and related conditions of the head and neck. STUDY DESIGN: A large national survey and administrative claims databases were examined to develop practice profiles and compile a physician supply for otolaryngology. A focus group of otolaryngologists provided information to model future scenarios. RESULTS: The current and predicted workforce supply and demographics are at a satisfactory level and are decreasing as a proportion of the increasing population. Empiric data analysis supports the diverse nature of an otolaryngologist's practice and the unique role for otolaryngologists that is not shared by many other providers. Together with the focus group results, the study points to areas for which more background and training are warranted. CONCLUSIONS: This study represents a first step in a process to form coherent workforce recommendations for the field of otolaryngology.

Use of computed tomography in the assessment of mandibular invasion in carcinoma of the retromolar trigone.

Carcinomas originating in the retromolar trigone (RMT) are uncommon and characterized by early spread. Determination of mandibular invasion is significant for planning therapy and determining prognosis. For oral cavity cancers in general, CT is reasonably accurate in assessing bone invasion. However, there is a paucity of information specifically addressing the value of CT in the RMT. In this study, the records of patients with biopsy-proven RMT carcinomas treated between 1984 and 1998 were reviewed with attention to preoperative CT scans and histopathologic findings during surgery. Half of the patients who were treated with primary resection had mandibular invasion. Bone invasion was not identified radiographically in 27% of patients with preoperative CT scans. The sensitivity of CT for bone involvement in RMT cancers was 50%, with a negative predictive value of 61.1%. The positive predictive value was 91.1%. These findings suggest that CT is a useful, but potentially inaccurate, predictor of bone invasion in the RMT.

Nitric oxide is a mediator of the late-phase response in an animal model of nasal allergy.

The presence of nitric oxide (NO) in the nose is well documented; however, the role of this molecule in nasal physiology is still poorly understood. Our laboratory has previously demonstrated that NO is a mediator of the immediate secretory response to an intranasal histamine challenge in a rat model of nasal allergy. Histamine challenge, however, does not elicit a late-phase response (LPR). To study the role of NO in the LPR, we developed a model of nasal allergy in which brown Norway rats are actively sensitized to the allergen ovalbumin and later challenged intranasally with either phosphate-buffered saline solution (vehicle), ovalbumin in vehicle, or ovalbumin and the NO synthase inhibitor N -nitro-l -arginine methyl ester. In each experiment, nasal lavage samples were collected 30, 120, 240, and 360 minutes after challenge. Lavage samples were analyzed for albumin content by ELISA, inflammatory cell concentration with a hemocytometer, and evidence of inflammation by light microscopy. Blocking NO synthesis with N -nitro-l -arginine methyl ester significantly inhibited both albumin exudation and inflammatory cell influx into the nasal cavity during the LPR. These data suggest that NO plays a role in the LPR of nasal allergy.

Nodal volume reduction after concurrent chemo- and radiotherapy: correlation between initial CT and histopathologic findings.

BACKGROUND AND PURPOSE: The role of concurrent chemoradiation for treatment of head and neck squamous cell carcinoma is expanding. We sought to evaluate the CT appearance of diseased and normal cervical lymph nodes before and after concurrent chemoradiation and to correlate lymph node volume reduction as revealed by CT with histopathologic findings of resected nodes. METHODS: Using concurrent chemoradiation, we treated seven patients with locally advanced head and neck squamous cell carcinoma. Our chemotherapeutic regimen consisted of cisplatin (100 mg/m2 body surface area administered on days 1 through 4 and 29 through 32) and 5-fluorouracil (1000 mg/m2 body surface area, administered on days 1 through 4 and 29 through 32). Radiotherapy was administered twice per day on dosing days 1 through 42 to a total dose of 7200 cGy to the primary tumor and 6000 cGy to the involved lymph nodes. Pre- and post-treatment CT scans were used to calculate lymph node volumes for all CT-positive (size criteria or extracapsular spread or both) diseased nodes (n = 19) and one normal node per patient (n = 7). Volume reduction was determined by CT results and correlated with the histopathologic findings of resected nodes. RESULTS: Average volume reduction (+/- standard error of the mean) for the 19 diseased nodes was 91%+/-4% and for the seven normal nodes was 55%+/-21% (P < .02, two-sided t test). Fifteen of 19 of the diseased lymph nodes showed extracapsular spread before treatment and none of 19 after treatment. The histopathologic findings of resected nodes included persistent tumor in one of the 19 diseased lymph nodes. Six of seven patients remained alive and disease-free, with an average follow-up duration of 24 months. CONCLUSION: Nodal volume reduction of greater than 90% was associated with eradication of tumor as assessed by histopathologic analysis of resected nodes. Serial CT scans obtained both before and after concurrent chemoradiation may be useful for predicting which patients will benefit from adjuvant surgical therapy.

Cytotoxic changes in hair cells secondary to pneumococcal middle-ear infection.

To determine whether the bacterial toxins associated with otitis media could induce morphologic changes in the organ of Corti, we inoculated the middle-ear cavities of healthy guinea pigs with either Streptococcus pneumoniae or sterile saline and then examined the organ of Corti histologically at 1, 2, and 3 weeks postinoculation. We found that the outer hair cells (OHCs) in the infected ears underwent several changes that were dependent on both the length of time following inoculation and also the position of the OHCs in the cochlea. At 2 weeks postinoculation, 7.0 to 20% of the OHC nuclei from the infected animals became very swollen, with the most significant swelling occurring in the basal turn. At 3 weeks postinoculation, 2.5 to 3.5% of the OHCs were missing in the infected animals, with the most significant loss occurring in the basal and middle turns. These results suggest that bacterial otitis media can produce cytotoxic changes in the cochlea. These changes may be a clinically significant factor in the temporary and permanent sensorineural hearing loss that has been associated with bacterial otitis media.

Allergy increases susceptibility to otitis media with effusion in a rat model. Second place--Resident Clinical Science Award 1998.

To investigate the possible relationship between allergy and otitis media with effusion (OME), we investigated the hypothesis that allergen presentation to the middle ear causes functional disruption of the eustachian tube predisposing to the development of OME. Thirteen of 19 Brown-Norway rats were sensitized to ovalbumin, and the remaining 6 served as nonallergic controls. To mimic subclinical exposure to allergen, we transtympanically injected ovalbumin at a dose (0.01 mg) that produced no changes detectable by otologic examination. Next, both allergic and nonallergic rats were exposed to transtympanic injection of either low-dose (10 microg/mL) or high-dose (100 microg/mL) lipopolysaccharide to simulate bacterial exposure. The allergic rats were found to have larger middle ear effusions when exposed to high-dose lipopolysaccharide as compared with the nonallergic controls. This response could be inhibited by diphenhydramine. We conclude that allergen presentation to the middle ear of allergic rats causes eustachian tube dysfunction predisposing to OME.

Systemic reactivation of otitis media with effusion in a rat model.

OBJECTIVE: This study addresses the interaction of bacterial antigens, specifically peptidoglycan-polysaccharide (PG-PS) and lipopolysaccharide (LPS), in the induction and reactivation of mucoid middle ear effusions. METHODS: Twenty-seven rats underwent eustachian tube obstruction before inoculation of the middle ear bulla with PG-PS. Three weeks later, after resolution of all middle ear effusions, 6 rats were randomly selected and euthanized as the first control group (control I). The remaining 21 animals were randomly assigned to 3 groups that received intravenous injections of Krebs Ringer (control II), PG-PS, and LPS, respectively. These rats were euthanized 2 days after intravenous injection. Middle ear mucin production and histologic changes were measured in all animals. RESULTS: The mean concentrations of mucin were 0.94 +/- 0.52 mg/mL, 0.41 +/- 0.87 mg/mL, 16.33 +/- 3.67 mg/mL, and 1.15 +/- 0.41 mg/mL in the control I, control II, PG-PS, and LPS groups, respectively. Thus the mean concentration of mucin in the middle ear lavage samples was significantly greater in rats that were injected intravenously with PG-PS than in rats in other groups (P < 0.05). Histologic analyses demonstrated a greater degree of goblet cell hyperplasia in the PG-PS group than in other groups. CONCLUSIONS: This is the first animal model of recurring otitis media with effusion in which a systemic injection of PG-PS was used to reactivate a middle ear effusion in rats previously primed with a transtympanic injection of PG-PS. This study suggests that after otitis media with effusion has resolved, it may be reactivated by the presence of bacterial antigens and/or cytokines in the systemic circulation.

Mucin production in the middle ear in response to lipopolysaccharides.

OBJECTIVE: This study examined the response of middle ear tissue to establish the lowest dose of lipopolysaccharide to induce mucin production in a rat otitis media model. METHODS: Twenty-six male Sprague-Dawley rats' eustachian tubes were obstructed before transtympanic inoculation of the bulla tympanica with 35 microL of Krebs Ringer or 1, 10, 100, or 1000 microgram/mL lipopolysaccharide. After 7 days the effusion and a lavage were collected for mucin ELISA measurement, and tissue was collected for histologic evaluation. RESULTS: Mucin secretion was significantly increased in the 100 microgram/mL 51.20 +/- 13.6 microgram/mL (SE) and 1000 microgram/mL 69.42 +/- 8.57 microgram/mL groups when compared with the Krebs Ringer control group 1.84 +/- 0.28 microgram/mL (P < 0.05). Histologic evaluation shows goblet cell metaplasia and hyperplasia in the middle ear epithelium in the 1000 and 100 microgram/mL groups. CONCLUSIONS: The histology and ELISA results suggest that a middle ear effusion is generated with a dose of lipopolysaccharide as low as 100 microgram/mL.

Non-insulin-dependent diabetic microangiopathy in the inner ear.

UNLABELLED: Hearing loss has long been associated with diabetes mellitus. Microangiopathy, associated with thickening of the basement membranes of small vessels, has been implicated as a major source of multiple system organ disease. OBJECTIVE: This study was designed to evaluate changes in basement membrane thickness in the inner ear of laboratory animals suffering from non-insulin-dependent diabetes mellitus (NIDDM) with, and without, exposure to moderate intensity noise exposure in an attempt to extrapolate the same disease process in humans. DESIGN: Spontaneously hypertensive-corpulent non-insulin-dependent rats (SHR/N-cp) were selected as a genetic model for the above study. Both lean and obese rats were used in this study. A genetically similar control group of animals (LA/N-cp) were used as controls. These animals express both the lean and obese phenotypes, but they lack the NIDDM gene. Forty-eight animals in each group were sacrificed at the end of the study. The cochleas were dissected and fixed. The basement membrane of the stria vascularis was examined using transmission electron microscopy. SETTING: This study was a laboratory-based, standard animal study. MAIN OUTCOME: This study was designed to show microangiography of the inner ear as related to NIDDM with, and without, obesity and noise exposure. RESULTS/CONCLUSIONS: NIDDM alone does not cause statistically significant basement membrane thickening; however, NIDDM in combination with obesity and/or noise exposure did show significant thickening and the combination of all three showed the greatest thickening. NIDDM appeared to be the greatest contributing factor.

The effects of amplitude modulation on acoustic reflex decay.

The temporal decay of the acoustic reflex provides the basis for an objective audiological test that differentiates cochlear from retrocochlear pathologies. The classic sign of a neural lesion is a rapid decay of the reflex under conditions of pure-tone stimulation for frequencies of 1,000 Hz and below. This restriction to lower frequencies is due to the fact that even normal ears show decay for higher-frequency signals. At present, it is unclear whether the acoustic reflex decay (ARD) seen in normal ears is related to frequency-specific channels or whether the critical variable is the timing information coded within the channels. This study examined ARD in subjects with normal hearing and middle ear function. The degree of ARD was measured for both modulated and unmodulated carrier frequencies of 500, 1,000, 2,000 and 4,000 Hz with amplitude modulation rates of 50-400 Hz. The dependent variable was the half-life of the decaying reflex (ARD 50%) over a 20-second stimulation interval. Significant ARD was present for high-frequency unmodulated carriers but not for low-frequency carriers. For all listeners, ARD was diminished for all modulated stimuli. The results of this study suggest that resistance to ARD is mediated by both the temporal aspects and frequency of a stimulus.

Role of nitric oxide in kainic acid-induced elevation of cochlear compound action potential thresholds.

Nitric oxide (NO) has specifically been found to mediate the effects of excitatory amino acids in the central nervous system (CNS). Excitatory amino acids are the primary neurotransmitters at the cochlear hair cell afferent nerve synapse. Recent studies in our laboratory demonstrate that NO synthase is an active enzyme in the spiral ganglion cells of the cochlea. Given our current understanding of neurotransmission in the cochlea, it is reasonable to postulate that the actions of NO in cochlear neuronal tissue are similar to the actions of NO in the CNS, and that NO acts as a neurotransmitter/neuromodulator in the cochlea. In addition, NO is implicated as a mediator of excitotoxicity in the CNS and may therefore play a similar role in excitotoxicity in the cochlea. To further elucidate the role of NO in cochlear excitotoxicity, this study investigated the effects of 7-nitroindazole (7-NI), a competitive inhibitor of neuronal nitric oxide synthase, with regard to kainic acid (KA)-induced elevation of compound action potential (CAP) thresholds. KA is a conformationally restricted analog of glutamate with well-known excitotoxic effects on SGC's and previously described inhibitory actions on cochlear CAP thresholds. In anesthetized gerbils, CAP thresholds were recorded before and after cochlear perfusions with control solutions of artificial perilymph solution and test solutions of KA. 7-NI was administered i.p. prior to KA perfusion in an effort to block its depolarizing and toxic effects. Results showed that cochlear perfusion with KA caused significant elevation (p < 0.05) of the mean CAP threshold. This threshold shift was significantly reduced (p < 0.05) in animals pretreated with 7-NI. These results indicate that NO is involved in the toxic effects on CAP thresholds elicited by KA in the cochlea.