Treatment of a floppy epiglottis with upper airway stimulation therapy.

PURPOSE: To evaluate the efficacy of upper airway stimulation therapy in patients with a floppy epiglottis who have experienced continuous positive airway pressure failure or intolerance. METHODS: A retrospective single-center cohort study was conducted. Patients who received an Inspire Upper Airway Stimulation system and had a 1-year follow-up were included. Baseline and one-year in-laboratory polysomnography examinations were performed. Patient characteristics, Epworth Sleepiness Scale scores and upper airway stimulation device settings were collected. RESULTS: A total of 75 patients were included, of whom 10 had a floppy epiglottis. Patients with a floppy epiglottis had a significant therapeutic response to upper airway stimulation therapy, similar to patients without a floppy epiglottis. According to the Sher's success criteria, 90% of patients with a floppy epiglottis and 68% of patients without a floppy epiglottis were responders to therapy (p = 0.149). In the floppy epiglottis group, the apnea-hypopnea index decreased from 35.1 ± 5.5 events/hour to 11.2 ± 11.3 events/hour (95% CI (15.0, 32.9), p < 0.001), similarly in the non-floppy epiglottis group, the decline was from 36.4 ± 8.3 events/hour to 14.4 ± 9.5 events/hour (95% CI (18.6, 25.2), p < 0.001, between groups p = 0.659). Comparable reductions were observed for the other respiratory parameters. CONCLUSION: Treatment of patients with obstructive sleep apnea and a floppy epiglottis can be challenging. Continuous positive airway pressure may aggravate the epiglottis collapse. Upper airway stimulation therapy can be considered an effective alternative treatment option for patients with a floppy epiglottis who have encountered either continuous positive airway pressure failure or intolerance.

The effect of velar collapse patterns on unilateral upper airway stimulation therapy.

PURPOSE: Hypoglossal nerve stimulation is a promising alternative therapy for patients with obstructive sleep apnea with continuous positive airway pressure intolerance or failure. Previous studies concluded that a velar complete concentric collapse might prohibit a good therapeutic outcome. However, certain patients have an upper velar anteroposterior collapse and a lower velar complete concentric collapse. The effect of this velar collapse pattern is unknown, preventing evidence-based decision-making for these patients. This study aimed to compare the results of upper airway stimulation therapy in these patients to patients with a pure anteroposterior velar collapse. METHODS: A retrospective single-center cohort study was performed. Patients were included who were implanted with an upper airway stimulation device and had a 1-year follow-up. RESULTS: Of 66 patients, 10 had an upper velar anteroposterior collapse and lower velar complete concentric collapse. Fifty-six patients had a complete or partial velar anteroposterior collapse. At follow-up, all respiratory outcomes were similarly changed between the two groups. The mean apnea and hypopnea index reduced equally (26.9 events/hour vs. 23.9 events/hour, 95% CI (-5.0, 11.0), p = 0.46). A similar decrease in the oxygen desaturation index of ≥ 4% was observed (12.0/hour versus 11.5/hour, 95% CI (-8.7, 9.7) p = 0.92) CONCLUSION: Patients with an upper velar anteroposterior collapse and a lower velar complete concentric collapse are suitable candidates for upper airway stimulation therapy. In these patients, the lower velum may represent a transition zone between the anteroposterior collapse of the upper velum and the lateral collapse of the oropharynx, instead of being a real concentric collapse.

Drug-induced sleep endoscopy while administering CPAP therapy in patients with CPAP failure.

STUDY OBJECTIVES: To study the pattern of upper airway collapse in patients with CPAP failure by performing DISE while administering CPAP therapy and to determine the reason for CPAP failure accordingly. METHODS: This observational retrospective study comprised 30 patients diagnosed with OSA and CPAP failure, who underwent DISE while administering CPAP therapy. During DISE, the upper airway was assessed with and without CPAP therapy using the VOTE classification. Additionally, a jaw thrust maneuver was performed, in order to mimic the effect of an additional mandibular advancement device (MAD) in combination with CPAP therapy. Consequently, the outcome of DISE was translated into a clinically relevant categorization. RESULTS: Eleven patients (37%) had a persistent anteroposterior (AP) collapse, including a collapse at velum, tongue base, or epiglottis level and multilevel collapse. Eight patients (27%) had a floppy epiglottis. Five patients (17%) had a persistent complete concentric collapse (CCC) and three patients had a persistent laryngeal collapse (10%). In three patients (10%), no airway collapse was found after CPAP administration. CONCLUSIONS: Based on the results of the reported study, in most cases, the potential cause of CPAP failure can be determined by this new diagnostic method. Consequently, suggestions can be made for additional therapy.

Photodynamic therapy in the treatment of multiple primary tumours in the head and neck, located to the oral cavity and oropharynx.

OBJECTIVES: Multiple primary tumours are a common problem in the head and neck cancer patients. Curative surgery or radiotherapy of these tumours can be very mutilating or even impossible. This study aims at evaluating meta-tetrahydroxy-phenyl chlorin-mediated photodynamic therapy for second or multiple primary tumours in the head and neck. DESIGN: Retrospective study of all patients with second or multiple primary tumours treated by photodynamic therapy over a 10-year period. SETTING: All patients were treated in the Netherlands Cancer Institute, a tertiary referral centre for the head and neck cancer patients. PARTICIPANTS: A total of 27 patients with 42 the second or the multiple primary head and neck tumours were treated by photodynamic therapy (0.15 mg/kg meta-tetrahydroxy-phenyl chlorin). MAIN OUTCOMES MEASURES: Cure rates. RESULTS: Twenty-eight of 42 tumours were cured (67%). Cure rates for stage I or in situ disease were 85%versus 38% for stage II/III. CONCLUSIONS: Cure rates for photodynamic therapy of the multiple primary head and neck tumours were lower than previously described for first primaries, but were still very encouraging for this difficult patient population. The high cure rate obtained in stage I multiple primaries emphasises the importance of a meticulous follow-up of patients treated for the head and neck cancer to detect new tumours at a curable stage.

Surgical technique--unwrapping the neck node levels around a sternocleidomastoid muscle bar: a systematic way of performing (modified) radical neck dissection.

AIM: Description of a systematic approach to the neck for removal of lymph node bearing tissues in levels I-V. METHOD: A (modified) radical neck dissection is divided in three steps: (1) Dissection of levels I-IV, (2) dissection of level V and (3) transection of SCM bar and finalisation of the dissection. The sternocleidomastoid muscle (SCM) is used as a "bar", around which the different neck levels can be systematically unwrapped, warranting permanent cranio-caudal tension of the neck specimen, while anatomical relations remain intact. RESULTS: In a group of 115 (modified) radical en bloc neck dissections with or without post-operative radiotherapy 10% regional recurrences, 2% post-operative chylous fistulas and < 5% post-operative wound infections occurred. The overall 5 years survival was 45% (95% confidence interval: 36-54%). CONCLUSION: A systematic unwrapping of lymph node levels around the sternocleidomastoid bar provides a reliable systematic method for performing (modified) radical neck dissections without a negative influence on clinical outcome.

The AMORE protocol as salvage treatment for non-orbital head and neck rhabdomyosarcoma in children.

AIM: To investigate the feasibility and outcome of the AMORE protocol as salvage treatment in paediatric head and neck rhabdomyosarcoma (HNRMS). METHODS: The AMORE protocol is a local treatment regimen, consisting of Ablative surgery, Moulage technique brachytherapy and surgical Reconstruction, scheduled in 1 week. Patients with recurrent or residual non-orbital HNRMS were eligible for AMORE salvage treatment. RESULTS: The procedure was feasible in nine out of 11 eligible patients. Five patients were treated for recurrent or residual parameningeal RMS after prior chemoradiation. Local complete remission was achieved in all five patients and maintained in four. Three patients are without evidence of RMS with a follow-up duration of 4-10 years. Two patients developed a distant relapse, together with a local recurrence in one. Both patients died of their disease. Four patients were included for recurrent non-parameningeal HNRMS. Long-term local control at the site of recurrence was obtained in all four patients (follow-up 5-10 years). CONCLUSIONS: The AMORE protocol is a feasible salvage strategy for non-orbital HNRMS even after external beam radiotherapy. The local salvage rate in this series is promising.

A novel local treatment strategy for advanced stage head and neck rhabdomyosarcomas in children: results of the AMORE protocol.

The AMORE protocol is a local treatment regimen for head and neck rhabdomyosarcomas (HNRMS), consisting of Ablative surgery, Moulage technique brachytherapy and surgical Reconstruction. The aim of AMORE is to intensify local treatment for children with HNRMS and to avoid external beam radiation therapy (EBRT) and its long-term sequelae. All children with primary irresectable, non-orbital HNRMS in whom EBRT was indicated, were evaluated for the feasibility of AMORE. In 20 children, AMORE was performed (15 with parameningeal disease and five with non-parameningeal disease). Complete remission was achieved in all 20 patients. Local complications were limited. 5 patients experienced a local relapse and 1 patient developed distant metastases. Estimated 5-year OS and EFS were 67.5 and 64.1% for the entire group, and 64.2 and 60.0% for the parameningeal subgroup. We conclude that the AMORE protocol is a feasible strategy, with a good local control rate. Long-term sequelae of EBRT might be avoided although, to date, the follow-up is too short for definitive conclusions regarding these sequelae.

[Early diagnosis and prevention of malignant tumors in the head and neck region]. / Vroegdiagnostiek en preventie van maligne tumoren in het hoofd-halsgebied.

In the Netherlands more than 2000 new patients with head and neck cancer are diagnosed annually. Most of these cancers are squamous cell carcinomas. The use of tobacco and alcohol are well established aetiologic factors. Head and neck cancers usually affect patients above the age of 40 years and are somewhat more common in men than in women. The type of the initial symptoms of head and neck cancer depends largely on the exact location. Often, these symptoms are rather aspecific. However, laryngeal cancer is an exception. In this site cancer usually presents at an early stage with sudden hoarseness. Hoarseness of more than three weeks' duration requires laryngoscopic examination. Particularly the cancers of the floor of the mouth and the borders on the tongue can be detected early because of the accessibility of these sites, which allows proper inspection and palpation. The most common clinical manifestation of oral cancer is an indurated ulcer. An oral ulcer present for more than three weeks is an indication for biopsy. The prognosis of head and neck cancer in general depends largely on the stage at diagnosis. Small cancers carry a much better prognosis after surgical removal or radiotherapy than larger ones.

Effect of cigarette smoking on gastropharyngeal and gastroesophageal reflux.

Gastropharyngeal reflux appears to be associated with various otolaryngological complaints. Cigarette smoking is known to affect adversely the defense mechanisms against reflux of acid gastric contents into the esophagus. To study the relationship between gastropharyngeal, as well as gastroesophageal, reflux and cigarette smoking, 15 subjects underwent 24-hour double-probe pH monitoring while smoking their daily amount of cigarettes. The percentage of time the pH was below 4 during the smoking period was significantly higher than the percentage of time the pH was below 4 during the nonsmoking period, proximal, at the level of the upper esophageal sphincter, as well as distal, above the lower esophageal sphincter. These findings demonstrate that smoking increases gastropharyngeal and gastroesophageal reflux. Smokers with complaints and disorders caused by reflux should therefore be advised to stop smoking in order to reduce reflux.

Lymphoma in the ear.

BACKGROUND: Malignant tumors of the ear are rare. The most common malignant tumors are squamous cell carcinomas and adenocarcinomas. Lymphoma in the ear is rare. METHODS: We report 2 cases of a primary presentation of a lymphoma of the ear. The literature since 1947 is reviewed. RESULTS: An 83-year-old woman with an anaplastic large cell lymphoma of the skin of the external auditory meatus and a 75-year-old man with a B-cell non-Hodgkin's lymphoma of the mastoid process are presented. The literature review shows that only 16 cases of lymphomas of the ear have been reported so far. CONCLUSIONS: In a case of therapy-resistant otitis and/or peripheral facial paralysis malignancy should be excluded by computer tomography of the mastoid. For histopathological diagnosis unfixed specimens are preferable. Uniform treatment of lymphomas of the ear has not been established.

High incidence of laryngopharyngeal reflux in patients with head and neck cancer.

OBJECTIVES: Laryngopharyngeal reflux may play a role in the etiology of squamous cell cancer of the head and neck and contribute to complications in head and neck cancer patients after surgery or during radiotherapy. STUDY DESIGN: Prospective study. METHODS: To investigate the incidence of laryngopharyngeal and gastroesophageal reflux in patients with head and neck cancer, ambulatory 24-hour double-probe pH monitoring was performed in 24 untreated patients with laryngeal or pharyngeal squamous cell carcinoma. In addition, 10 patients who had been irradiated in the head and neck area were analyzed for reflux to study the effect of radiotherapy on reflux. RESULTS: Only 4 of the 24 head and neck cancer patients (17%) had neither pathological laryngopharyngeal nor gastroesophageal reflux. Esophageal acid exposure was abnormal in five patients and acid exposure at the level of the upper esophageal sphincter was abnormal in four patients. Eleven patients had pathological reflux in both areas. Irradiated patients did not differ from the untreated patients considering the incidence of pathological laryngopharyngeal or gastroesophageal reflux. CONCLUSIONS: The data obtained in this study indicate that reflux is a common event in head and neck cancer patients.

Evidence for recurrent laryngeal nerve contribution in motor innervation of the human cricopharyngeal muscle.

OBJECTIVE: To study the functional motor nerve supply of the upper esophageal sphincter in humans. STUDY DESIGN: Intraoperative electromyographic study. METHODS: The contribution of the recurrent laryngeal nerve and the pharyngeal plexus in the motor nerve innervation of the cricopharyngeal muscle and the inferior pharyngeal constrictor muscle was examined intraoperatively. RESULTS: Electromyography showed that there is a considerable overlap in the innervation of the cricopharyngeal muscle and the inferior pharyngeal constrictor muscle. The recurrent laryngeal nerve functionally contributes to the motor innervation of the cricopharyngeal muscle in all patients and contributes to the motor innervation of the inferior pharyngeal constrictor muscle in most patients. The pharyngeal plexus functionally contributes to the motor innervation of the inferior pharyngeal constrictor muscle but does not always contribute to the motor innervation of the cricopharyngeal muscle. CONCLUSIONS: This is the first report which provides evidence that the recurrent laryngeal nerve functionally contributes to the motor innervation of the cricopharyngeal and inferior pharyngeal constrictor muscle. Furthermore, this study shows that intraoperative electromyography in humans is a feasible method to analyze the physiology of the motor innervation of the upper esophageal sphincter.

Plasma retinoid levels in head and neck cancer patients: a comparison with healthy controls and the effect of retinyl palmitate treatment.

Vitamin A and related compounds, also known as retinoids are thought to play a role in the development of head and neck cancer. We measured levels of the major retinoids, retinol, all-trans retinoic acid, 13-cis retinoic acid and 13-cis-4-oxo retinoic acid in plasma of head and neck cancer patients in comparison with controls without cancer. No differences were found between plasma levels of these retinoids between 25 head and neck cancer patients and 21 controls. Mean baseline levels for the patients were 2458. 6.0, 6.4 and 8.6 nM for retinol, all-trans retinoic acid, 13-cis retinoic acid and 13-cis-4-oxo retinoic acid, respectively. In addition, we selected 10 patients from the chemoprevention trial Euroscan and measured the effect on retinoid levels of 300,000 I.U. daily retinyl palmitate intake during 1 month. Medication caused significant elevations in retinol levels (1.2 fold), all-trans retinoic acid (2.2 fold) and its metabolites 13-cis retinoic acid (5.8 fold) and 13-cis-4-oxo retinoic acid (8.9 fold). Because of its high increase in levels, 13-cis-4-oxo retinoic acid seems a good candidate to serve as a suitable marker to monitor patient compliance in future chemo-prevention trials involving retinoids. No relations were found between the occurrence of side-effects of retinyl palmitate and retinoid levels during treatment. However, the two patients who developed side-effects had the highest pre-treatment levels of 13-cis retinoic acid and 13-cis-4-oxo retinoic acid, suggesting that retinoid toxicity is associated with relatively high basal retinoid metabolism.

Exfoliated oral cell messenger RNA: suitability for biomarker studies.

The efficacy of chemoprevention trials can be improved by the use of biomarkers of carcinogenesis that serve as surrogate end points. The aim of this study was to assess the perspectives of using mRNA isolated from oral exfoliated cells for biomarker research in chemoprevention of upper aerodigestive tract cancer. When using reverse transcription-PCR in combination with Southern blotting and hybridization, it was possible to detect transcripts from only five cells. With the quantitative RNase protection assay, we could only detect highly abundant transcripts. The integrity of the RNA was verified by Northern blotting, which showed a variable degree of degradation, depending on the gene studied. Interestingly, although specific transcripts were found to be intact to a certain extent, the rRNA appeared to be completely degraded, suggesting that a specific protein synthesis shut-off mechanism exists in terminally differentiated oral epithelial cells. Altogether, this differential RNA degradation makes accurate measurement of transcript levels of most genes, as determined in exfoliated oral cells, unreliable. Because this RNA degradation process is likely to start before the cells are shed from the tissue, the results of measurements of transcript levels in biopsies of oral tissue should be interpreted with caution.

All-trans retinoic acid induced gene expression and growth inhibition in head and neck cancer cell lines.

Retinoids are natural and synthetic analogues of vitamin A and have proven activity in various types of cancer. As for head and neck squamous cell cancer (HNSCC), retinoids are especially active in leukoplakia and in preventing second primary cancers. The aim of this study was to assess the growth inhibiting activity of all-trans retinoic acid (all-trans RA) in a panel of six head and neck squamous cell cancer cell lines and to correlate this response to the mRNA expression of factors related to differentiation and receptor mediated signal transduction. Three lines showed minimal, two moderate and one strong growth inhibition after 72 h exposure to all-trans RA. Three lines with a dissimilar response were selected for further studies, the measurement of mRNA expression by northern blotting. It was found that neither the expression nor the induction of retinoic acid receptor (RAR)-alpha and -gamma and retinoic X receptor-alpha mRNA war related to sensitivity. The mRNA expression of RAR-beta was too low to be measured in the three cell lines. The most sensitive cell line was, however, the only one that expressed mRNA of squamous differentiation markers. These data suggest a relationship between the retinoid sensitivity profile and the degree of cellular differentiation.

Simultaneous analysis of retinol, all-trans- and 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in plasma by liquid chromatography using on-column concentration after single-phase fluid extraction.

A reversed-phase high-performance liquid chromatographic method for the simultaneous analysis of retinol, all-trans-retinoic acid, 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma and cell culture medium is described. Sample preparation involves precipitation of proteins and extraction of retinoids with 60% acetonitrile. After centrifugation, the acetonitrile content of the supernatant is reduced to 45%, allowing on-column concentration of analytes. Injection volumes up to 2.0 ml (equivalent to 0.525 ml of sample) can be used without compromising chromatographic resolution of all-trans-retinoic acid and 13-cis-retinoic acid. Retinoids were stable in this extract and showed no isomerization when stored in the dark in a cooled autosampler, allowing automated analysis of large series of samples. Recoveries from spiked plasma samples were between 95 and 103%. Although no internal standard was used, the inter-assay precision for all retinoids was better than 6% and 4% at concentrations of 30 nM and 100 nM, respectively. The method is a valuable tool for the study of cellular metabolism of all-trans-retinoic acid, as polar metabolites of this compound can be detected with high sensitivity in cell culture media.

Retinoid metabolism and all-trans retinoic acid-induced growth inhibition in head and neck squamous cell carcinoma cell lines.

Retinoids can reverse potentially premalignant lesions and prevent second primary tumours in patients with head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been reported that acquired resistance to all-trans retinoic acid (RA) in leukaemia is associated with decreased plasma peak levels, probably the result of enhanced retinoid metabolism. The aim of this study was to investigate the metabolism of retinoids and relate this to growth inhibition in HNSCC. Three HNSCC cell lines were selected on the basis of a large variation in the all-trans RA-induced growth inhibition. Cells were exposed to 9.5 nM (radioactive) for 4 and 24 h, and to 1 and 10 microM (nonradioactive) all-trans RA for 4, 24, 48 and 72 h, and medium and cells were analysed for retinoid metabolites. At all concentrations studied, the amount of growth inhibition was proportional to the extent at which all-trans-, 13- and 9-cis RA disappeared from the medium as well as from the cells. This turnover process coincided with the formation of a group of as yet unidentified polar retinoid metabolites. The level of mRNA of cellular RA-binding protein II (CRABP-II), involved in retinoid homeostasis, was inversely proportional to growth inhibition. These findings indicate that for HNSCC retinoid metabolism may be associated with growth inhibition.

Standardization of counting micronuclei: definition of a protocol to measure genotoxic damage in human exfoliated cells.

The proportion of exfoliated buccal mucosal cells with micronuclei gives the opportunity to assess sensitivity to gamma-radiation and genotoxic compounds and in addition to monitor the effectiveness of cancer intervention strategies. So far, results on counting micronuclei in various publications are difficult to compare because of differences in methods used, especially with regard to microscopical magnification used and number of cells counted. The aims of this study were (i) to define a protocol for counting micronuclei; (ii) to assess the feasibility of manually counting micronuclei; and (iii) the assessment of inter- and intra-patient variability of the number of micronuclei. We propose the definition of a strict protocol on counting micronuclei, with regard to cytological preparation, definition of micronuclei, instrumentation, sampling of cells in a cytological specimen and sample size. Such a strict protocol is a prerequisite for counting micronuclei in exfoliated cells to get a reproducible and sensitive indicator of exposure and for cancer risk. Although the inter- and intra-observer reproducibility of counting micronuclei per 1000 cells using such a protocol is well, we show that the variability among 10 assessments of micronuclei per 1000 cells taken sequentially from a sample size of 10,000 nuclei of the same specimen can be enormous (coefficients of variation varied in seven individuals studied between 42.1 and 102.9%). Based on the observed low frequencies varying from 1.2 to 5.2 micronuclei per 1000 cells and the variation found, we conclude that at least 10,000 exfoliated cells should be screened to monitor a significant reduction of 50% in the number of micronuclei (for a patient with an initial frequency in the micronuclei frequency range given). Since it takes approximately 7 h to evaluate this number of cells, it is also concluded that counting of micronuclei requires automation.

[Life-threatening angioedema as a side effect of angiotensin-converting-enzyme (ACE) inhibitors]. / Levensbedreigend angio-oedeem als bijwerking van angiotensine-'converting'-enzym (ACE)-remmers.

During the past years, angioedema occurring in association with angiotensin converting enzyme (ACE) inhibitors is seen more and more often. This is due to the increasing use of these drugs for hypertension and congestive heart failure. If the diagnosis is missed and prescription of the ACE inhibitor is prolonged, recurrent and more severe episodes of angioedema may occur. In case of involvement of the upper airway and respiratory distress, the condition may be life-threatening. We demonstrate three such patients, men of 84, 73 and 63 years old. First of all, the airway should be secured. Administration of epinephrine may be indicated. Further use of ACE inhibitors is contraindicated.