Lanny G. Close

PIK3CA Mutations in Head and Neck Squamous Cell Carcinoma

Purpose: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic α (PIK3CA) gene in several human solid tumors. Although gene amplifications of PIK3CA have been reported in head and neck squamous cell carcinoma (HNSCC), small mutation of the gene has not been evaluated in HNSCC previously. In this study, we examined the mutation frequency of PIK3CA in HNSCC. Experimental Design: More than 75% of the somatic mutations of PIK3CA are clustered in the helical (exon 9) and kinase domains (exon 20). To investigate the possible role of PIK3CA in HNSCC tumorigenesis, exons 1, 4, 5, 6, 7, 9, and 20 of the gene were analyzed by direct genomic DNA sequencing in 38 HNSCC specimens. Results: We identified four missense mutations in the seven exons of PIK3CA from 38 HNSCC specimens (11%). Three of the four mutations (i.e., H1047R, E542K, and E545K) have been previously reported as hotspot mutations. The remaining novel mutation, Y343C, is identified at exon 4 nucleotide 1028 A → G. Three of the four mutations were shown to be somatic, whereas the fourth mutation (H1047R) was identified in a cell line. Interestingly, three of the four mutations identified were in pharyngeal cancer samples. Conclusions: These data provide evidence that oncogenic properties of PIK3CA contribute to the carcinogenesis of human head and neck cancers, especially in pharyngeal cancer. A specific kinase inhibitor to PIK3CA may potentially be an effective therapeutic reagent against HNSCC or pharyngeal cancer in particular.

Ototoxicity of low- and moderate-dose cisplatin

Twenty‐four patients with head and neck neoplasms were prospectively evaluated for cisplatin (DDP)‐induced ototoxicity. Patients were selected from a larger population based on the uniformity of their chemotherapy regimen, renal status, lack of prior or concurrent exposure to ototoxic agents, and availability for repetitive audiometric testing in the same setting. Scanning electron microscopy of the inner ear was performed on four temporal bones. Hearing impairment was found to be dose‐related, irreversible within the confines of the study period, and primarily in the higher frequencies. Vestibular toxicity was rare and well‐documented by our testing methods in only one patient. Based on the results of this study, and a review of animal and human data on DDP ototoxicity, the authors concluded that ototoxic screening should be reserved for patients defined as “at risk” and those patients receiving more than 400 mg of DDP under the conditions stated in this report. Cancer 56: 1934‐1939, 1985.

Endoscopic paranasal sinus surgery: Indications and considerations

Recently, American otolaryngologists have become increasingly interested in endoscopic paranasal sinus surgery. This trend has been beneficial, because it has enhanced the understanding of the anatomy and pathophysiology of the sinuses. However, as with the introduction of any new surgical technique, it takes both time and experience to acquire the skills necessary to perform this procedure. To evaluate the state of endoscopic sinus surgery, we analyzed the experience of one of the authors with 100 consecutive patients undergoing therapeutic endoscopic sinus surgery over 23 months. With an average follow‐up of 5 months (range: less than 1 month to 20 months), 14 patients had minor complications. The most common complication was synechia between the middle turbinate and the lateral nasal wall (six patients), resulting in revision surgery in four patients. Eighty‐three patients were judged as having significantly improved after surgery, while ten were improved but had one episode of sinusitis postoperatively. The results of this series suggest that endoscopic paranasal sinus surgery is an efficacious advance in the treatment of sinusitis, given the limitations discussed in this report.

FEESST: A New Bedside Endoscopic Test of the Motor and Sensory Components of Swallowing

We here introduce an office or bedside method of evaluating both the motor and sensory components of swallowing, called fiberoptic endoscopic evaluation of swallowing with sensory testing (FEESST). FEESST combines the established endoscopic evaluation of swallowing with a technique that determines laryngopharyngeal (LP) sensory discrimination thresholds by endoscopically delivering air pulse stimuli to the mucosa innervated by the superior laryngeal nerve. Endoscopic assessment of LP sensory capacity followed by endoscopic visualization of deglutition was prospectively performed 148 times on 133 patients with dysphagia over an 8-month period. The patients had a variety of underlying diagnoses, with stroke and chronic neurologic disease predominating (n = 94). Subsequent to LP sensory testing, a complete dysphagia evaluation was conducted. Various food and liquid consistencies were dyed green, and attention was paid to their management throughout the pharyngeal stage of swallowing. Evidence of latent swallow initiation, pharyngeal pooling and/or residue, laryngeal penetration, laryngeal aspiration, and/or reflux was noted. Recommendations for therapeutic intervention were based on information obtained during the FEESST and often involved the employment of compensatory swallowing strategies, modification of the diet or its presentation, placement on non-oral feeding status, and/or referral to other related specialists. All patients successfully completed the examination. In 111 of the evaluations (75%), severe (>6.0 mm Hg air pulse pressure [APP]) unilateral or bilateral LP sensory deficits were found. With puree consistencies, 31% of evaluations with severe deficits, compared to 5% of evaluations with either normal sensitivity or moderate (4.0 to 6.0 mm Hg APP) LP sensory deficits, displayed aspiration (p <.001, χ2 test). With puree consistencies, 69% of evaluations with severe deficits, compared to 24% with normal or moderate deficits, displayed laryngeal penetration (p <.001, χ2 test). FEESST allows the clinician to obtain a comprehensive bedside assessment of swallowing that is performed as the initial swallowing evaluation for the patient with dysphagia.

Evidence of ige-mediated hypersensitivity in allergic fungal sinusitis†

Despite documentation of specific immunologic hypersensitivity in a few case reports, controversy continues as to the role of allergy versus true infection in the clinical entity of allergic fungal sinusitis (AFS). Using a modified radioallergosorbent test (RAST) to multiple fungal antigens, 16 patients meeting the histologic criteria of AFS and with positive fungal cultures were compared to 5 control patients with similar preoperative clinical findings but without histologic or culture evidence of AFS. All patients were immunocompetent and none demonstrated histologic evidence of tissue invasion. All AFS patients were RAST-positive to at least one fungal antigen in the family of their cultured organism with positive defined as class 2 or greater. No control patient was RAST-positive to either dematiaceous or Aspergillus fungal antigens. Thus, modified RAST testing can aid in the routine clinical diagnosis of AFS, and it provides further serologic evidence for a type I hypersensitivity in the pathogenesis of AFS.

Endoscopic management of frontal sinus disease

Depending on the pathologic process, the treatment of frontal sinus disease has consisted of obliteration or ablation of the sinus, or restoration of drainage into the nose. Intranasal endoscopic enlargement of the frontal recess and ostium, and removal of disease from the medial aspect of the frontal sinus offers a minimally invasive alternative to previous operations in selected patients. To better understand the indications, limitations, and potential problems with this operation, our experience with endoscopic frontal sinusotomy in 36 patients over a 30‐month period is reported. During the follow‐up period, 21 patients had complete resolution of all symptoms, 11 patients were improved but had at least one episode of sinusitis or headache post‐operatively, and 3 patients were worse, 2 of whom required frontal sinus obliteration for control of disease. Although endoscopic frontal sinusotomy appears to be a useful alternative to traditional frontal sinus procedures in selected patients, the reader is cautioned that such surgery is technically difficult and has not yet stood the test of time required of any frontal sinus operation.

The Safety of Flexible Endoscopic Evaluation of Swallowing with Sensory Testing (FEESST): An Analysis of 500 Consecutive Evaluations

We assessed the safety of a new office or bedside method of evaluating both the motor and sensory components of swallowing called flexible endoscopic evaluation of swallowing with sensory testing (FEESST). FEESST combines the established endoscopic evaluation of swallowing with a technique that determines laryngopharyngeal sensory discrimination thresholds by endoscopically delivering air-pulse stimuli to the mucosa innervated by the superior laryngeal nerve. Endoscopic assessment of laryngopharyngeal sensory capacity followed by endoscopic visualization of deglutition was prospectively performed 500 times in 253 patients with dysphagia over a 2.5-year period in a tertiary care center. The patients had a variety of underlying diagnoses, with stroke and chronic neurological disease predominating (n= 155). To determine the safety of FEESST, the presence of epistaxis, airway compromise, and significant changes in heart rate before and after the evaluation were assessed. Patients were also asked to rate the level of discomfort of the examination; 498 evaluations were completed. There were three instances of epistaxis that were self-limited. There were no cases of airway compromise. There were no significant differences in heart rate between pre- and posttest measurements (p > 0.05). Eighty-one percent of patients noted either no discomfort or mild discomfort as a result of the examination. In conclusion, FEESST is a safe method of evaluating dysphagia in the tertiary care setting and may also have application for the chronic care setting.

Laryngeal Adductor Reflex and Pharyngeal Squeeze as Predictors of Laryngeal Penetration and Aspiration

Objectives The contribution of laryngopharyngeal (LP) sensory deficits to the outcome of swallowing and the relationship between sensory and motor deficits in the laryngopharynx is unclear. The study purpose is to determine if patients with LP sensory and motor deficits are at increased risk for laryngeal penetration and aspiration during swallowing, and to determine the relationship between pharyngeal motor weakness and LP sensory deficits.

Silent laryngopharyngeal sensory deficits after stroke

Dysphagia and aspiration are two devastating sequelae of stroke. Recent work has shown that laryngopharyngeal (LP) sensory deficits are associated with aspiration in stroke patients with dysphagia. The phenomenon of silent LP sensory deficits, where the patient exhibits no subjective or objective evidence of dysphagia, yet has an LP sensory deficit, has not been previously described. The aim of this study was to evaluate the sensory capacity of the laryngopharynx in stroke patients who had no subjective or objective complaints of dysphagia. We determined the sensory threshold in the laryngopharynx using air pulse stimulation of the mucosa of the pyriform sinus and aryepiglottic fold. Eighteen stroke patients (mean age 65.6 ± 11.5 years) and 18 age-matched controls were prospectively evaluated. Normal thresholds were defined as <4.0 mm Hg air pulse pressure (APP). Deficits were defined as either a moderate impairment in sensory discrimination thresholds (4.0 to 6.0 mm Hg APP) or a severe sensory impairment (>6.0 mm Hg APP). Stroke patients were followed up for 1 year to determine the incidence of aspiration pneumonia (AP) as verified by chest radiography. In 11 of the stroke patients studied, either unilateral (n = 6) or bilateral (n = 5) severe sensory deficits were identified. The elevations in sensory discrimination thresholds were significantly greater than those in age-matched controls (7.1 ± 0.6 mm Hg APP versus 2.5 mm Hg APP; p < .01, Wilcoxon score). Among patients with unilateral deficits, sensory thresholds were severely elevated in all cases on the affected side compared with the unaffected side (p < .01, Wilcoxon score). Moreover, the sensory thresholds of the unaffected side were not significantly different from those of age-matched controls. Aspiration pneumonia did not occur in the patients with normal LP sensation or in the patients with unilateral severe LP sensory deficits. However, in the 5 patients with bilateral, severe LP sensory deficits, 2 developed AP, both within 3 months of their LP sensory test. The results of this study showed, for the first time, that stroke patients without subjective or objective clinical evidence of dysphagia could have silent LP sensory deficits. These impairments could contribute to the development of AP following stroke. The findings in this study suggest that LP sensory discrimination threshold testing should not be restricted only to patients with clinical dysphagia.

Laryngopharyngeal Sensory Deficits in Patients with Laryngopharyngeal Reflux and Dysphagia

There are no reliable means of quantifying the edema that results from acid exposure to the posterior larynx in patients with laryngopharyngeal reflux (LPR). However, it is possible to quantify laryngopharyngeal sensitivity in these patients by endoscopic administration of air pulses to the laryngeal mucosa in order to elicit the laryngeal adductor reflex. The purpose of this study was to determine whether patients with LPR have sensory deficits in the laryngopharynx, and whether treatment of these patients with a proton pump inhibitor (PPI) results in resolution of sensory deficits. Flexible endoscopic evaluation of swallowing with sensory testing was prospectively performed in 54 patients with dysphagia without neurologic disease and in 25 healthy controls. The laryngopharyngeal sensory level, posterior laryngeal edema, and LPR were assessed. We defined LPR as passage of food material from the esophageal inlet retrograde into the hypopharynx. Patients with LPR were placed on 3 months of omeprazole or lansoprazole and then retested. Patients without LPR were placed on H2 blockers for 3 months and then retested. In the dysphagia group, 48 of 54 patients (89%) had edema of the posterior larynx, and 42 of 54 (78%) had laryngopharyngeal sensory deficits. We noted LPR in 38 of 54 (70%). In the control group, 1 of 25 subjects (4%) had edema, sensory deficits, and LPR. The differences in incidence of edema, sensory deficits, and LPR between the dysphagia group and the control group were significant (p < .001, χ2 test). Twenty-three patients with LPR placed on a PPI returned for follow-up, with improvement in laryngeal edema in 14 of the 21 (67%) who had pretreatment edema and resolution of sensory deficits in 15 of the 19 (79%) who had pretreatment deficits. In the non-LPR, non-PPI group, 11 of 16 patients returned for follow-up, with improvement in laryngeal edema in none of the 11 and improvement in sensory deficits in 1 of the 11 (9.1%). The differences in improvement in laryngeal edema and sensory deficits between the LPR, PPI group, and the non-LPR, non-PPI group were significant (p < .01, Fishers exact test). We conclude that patients with dysphagia and edema of the posterior larynx as a result of LPR have sensory deficits in the laryngopharynx. Treatment of these patients with a PPI appears to result in resolution of laryngopharyngeal edema and improvement of sensory deficits, both subjectively and objectively.