Awareness of general practitioners towards treatment of laryngopharyngeal reflux: a British survey.

OBJECTIVE: Patients with acid reflux can occasionally present with atypical symptoms such as globus pharyngeus, constant throat clearing, chronic cough, hoarseness, catarrh, choking episodes or asthma-like symptoms. The aim of this survey was to determine whether general practitioners are aware of the atypical manifestations of reflux and the differences in treatment between laryngopharyngeal reflux and gastroesophageal reflux. DESIGN: Questionnaire Survey. SETTING: Primary Care RESULTS: One hundred and sixty general practitioners who routinely refer patients to our Department of Otolaryngology were selected and a postal survey was conducted. One hundred and fifty of these responded (94% response rate). The commonest symptoms for which proton pump inhibitors are prescribed are heartburn (65%), followed by a combination of heartburn and other symptoms (15%), chronic cough (4%), choking episodes (4%), asthma-like symptoms (3%), hoarseness (2%), globus (2%), catarrh (1%), dysphagia (1.5%), frequent throat clearing (1.5%), halitosis and/or bitter taste (1%). CONCLUSIONS: Our results suggest that the majority of the general practitioners surveyed are unaware of the entity laryngopharyngeal reflux or reflux symptom index. More awareness is required in the primary care setting for early recognition of patients with suspected laryngopharyngeal reflux.

Expression of retinoic acid receptors in squamous cell carcinomas and their possible implication for chemoprevention.

Retinoic acid and its natural and synthetic analogs (retinoids) affect a wide array of biological processes. Retinoids are used in the treatment of many skin diseases and are promising drugs for several cancers. Most of their actions are thought to result from changes in gene expression which is caused via nuclear retinoic acid receptors and retinoid X receptors. We conducted a study to determine whether the expression of these receptors is different in malignant tumors and tumor cell lines versus normal tissue. We performed reverse transcription PCR from 29 tissue specimens of squamous cell carcinomas and one melanoma of the head and neck, as well as from 13 cell lines established from head and neck cancer. We were looking for the expression pattern of RAR alpha, beta, gamma and RXR alpha. Only RAR gamma was expressed 100% in cell lines and tissue specimens. RAR beta showed 100% expression in tissue specimens whereas 54% expression in cell lines was seen. All other receptors were diminished in their expression. In the positive controls all receptors were expressed at 100%. The expression of RAR alpha and RAR beta was partially lost in cell lines established from squamous cell carcinoma of the head and neck. The 100% expression of RAR beta in tissue samples versus 54% in cell lines can be explained by the clonal growth of malignant cells in cell lines and also possible "contamination" by normal cells in the tissue specimen. In concordance with the literature it seems that RARa and beta play a pivotal role in mediating the response to retinoids.

Immune defects in patients with head and neck cancer.

Any deficiency or suppression of the immune response in head and neck cancer patients might be due to genetic factors of the host (patient factors), to tumor antigens (tumor factors) or to the medical treatment such as irradiation, anesthesia, major surgery or cytokine therapy (treatment factors). In order to achieve an effective adjuvant immunotherapy a thorough analysis of the immune situation is a prerequisite. With the increasing knowledge of the fine interactions with the immune system, the armamentarium has increased over the years. At the beginning only skin testing and T- and B-cell numbers were analyzed, whereas today a correlation of cell numbers, distribution and function is feasible.

Coexpression of epidermal growth factor receptor and TGF-alpha and survival in upper aerodigestive tract cancer.

In order to find a prognostic marker for the course of disease in head and neck cancer we hypothesized that patients with rapid disease progress would produce increased levels of transforming growth factor alpha (TGF-alpha) and its cell surface receptor, epidermal growth factor receptor (EGFR). Using molecular biological techniques, we examined the incidence of TGF-alpha and EGFR overexpression in 43 patients with tumors of the head and neck. The expression data was correlated with the course of disease in a 4 year follow-up. The tumors were classified into four groups according to the EGFR status: Group 1, no expression for EGFR (15 samples); group 2, expression level 10 for EGFR (18 samples); group 3, expression level 50 for EGFR (7 samples) and group 4, expression level 100 for EGFR (3 samples). Expression for the TGF-alpha protein was only detected in group 4. There was a significant correlation with EGFR/TGF-alpha overexpression in group 4 and survival compared when with group 3 (p < 0.01) and group 1 (p < 0.05). The mean survival for group 1 to 4 was 27, 23, 34 and 10 months, respectively. The analysis of all patients revealed that the patients who expressed EGFR as well as TGF-alpha had the poorest prognosis. Increased production of TGF-alpha and EGFR in tumors of the head and neck may serve both as a marker for tumor progression and as a target for therapy (e.g. inhibition of the autocrine loop, blockage of TGF-alpha binding).

Oncogenes related to head and neck cancer.

Cancer has been defined as a fundamental disorder of cellular growth control. Which arises in some cells through changes in genes (DNA-level: geneamplification, mutation and rearrangement) or their expression (RNA- and protein-level), and gives these cells a growth advantage in comparison to the surrounding cells. Since the last decade we know the identity of these genes and the nature of the changes they underwent in the cancer cell. Only a few of the known oncogenes play a role in head and neck cancer. These are the EGFR (epidermal growth factor receptor), c-myc, the ras gene family, int-2, hst- 1 and bcl- 1. In some clinical disorders, like childhood neuroblastoma and breast cancer, oncogenes play already an important role in tumor staging as well as a prognostic parameter. The aim for the future is the therapeutic application of oncogenes better known as gene therapy.

HIV-1-induced immune suppression may result from autoimmune disorders including anti-SLWDQ autoantibodies.

We have previously unravelled the striking SLWDQ pentapeptide identity between HIV-1 env gp120 and the CD4 molecule. We show here that this pentapeptide is required for the functioning of the co-stimulatory MHC-CD4 signal in T4-cell activation since it suppresses antigen-induced T-cell proliferation. Moreover, concerning the MHC class II counterpart, the LNGQEETGVVSTN sequence which strongly inhibits T-cell immune activation is likely to be part of the functional site of the molecule. Interestingly the MHC/gp120 homology described by Young overlaps this MHC region. We further report that the gp120 SLWDQ peptide triggers an immune reaction which is both humoral (anti-SLWDQ antibodies) and cellular (CTLs against autologous targets carrying the pentapeptide) in HIV-1 infected individuals. Finally, anti-SLWDQ antibodies from patients sera purified by column chromatography strongly inhibit antigen-induced immune T-cell activation. This result led us to postulate that these antibodies found in high titers in HIV-1 infected individuals could contribute to set up the progressive systemic immune T-cell suppression characterizing AIDS.

Critical sites: a semantic approach to protein sequences. Application to the HIV-1 envelope molecule.

We have designed two software systems allowing the study of proteins through a comparison to those stored in data banks. The first one, "Automat", locates in a systematic manner all identities shared by a given protein and the proteins in a data bank. The second, "Critic" enables the selection of specific segments in a given molecule by comparing them with those gathered in a data bank. These sites were termed "critical" since they mostly correspond to functional sites (active sites) of the well-known proteins which were studied with the aid of this program (somatostatin, insulin, IL2, etc). Automat allowed us to reveal homologies between HIV-1 and the CD4, which have remained unsolved until now. These similitudes proved to be critical sites (according to Critic). The putative involvement of these sites in the physiopathological processes as induced by HIV-1 are worth considering since the results of our experiments are consistent with this assumption.

Homeostasis of chemokines, interferon production and lymphocyte subsets: implications for AIDS pathogenesis.

Certain individuals with elevated levels of macrophage inflammatory protein (MIP)1 alpha, MIP1 beta and RANTES expression appear to be resistant to human immunodeficiency virus (HIV) infection. In this work, we demonstrate that chemokines production by peripheral blood mononuclear cells (PBMCs) are homeostatic parameters varying from one individual to another, and we define optimized experimental conditions to reproducibly assess these parameters. We also studied alpha- and gamma-interferons (IFN alpha and IFN gamma, respectively) which have been implicated in the pathogenesis of acquired immunodeficiency syndrome (AIDS). The kinetics of production of all these cytokines by fresh PBMCs were determined upon stimulation with phytohemagglutinin (PHA), staphylococcus enterotoxin b (SEB) and purified protein derivative (PPD). RANTES and MIP1 alpha are produced early in response to activation, followed by MIP1 beta, (alpha-interferon, gamma-interferon, alpha IFN, gamma-IFN alpha and IFN alpha and gamma. These results suggest that using our methodology, chemokines levels can be reliably determined, permitting the performance of accurate genetic studies using PBMCs from various cohorts (siblings or AIDS related cohorts).

Pigmentation, anesthesia, behavioral factors, and salicylate uptake.

In four experiments, 54 pigmented rats were used to examine the time course of sodium salicylate uptake in serum, cerebrospinal fluid, and perilymph. Subjects were tested under sodium pentobarbital anesthesia or while conscious. Compared with previously reported data from albino rats, pigmented subjects generally showed increased salicylate uptake. Moreover, the data suggested two different, time-dependent clearance mechanisms in conscious animals not observed in anesthetized rats. Daily injections of salicylate did not produce an accumulation of salicylate in serum. Systematically higher levels of salicylate were observed in perilymph compared with cerebrospinal fluid. Behavioral procedures, including water deprivation and conditioned suppression of ongoing drinking levels, had no effect on salicylate levels.

The role of flexible endosonography in diagnostic imaging of carcinomas of the oral cavity and oropharynx.

Currently-used imaging methods often fail to depict carcinomas of the oral cavity and oropharynx properly. Scanning these tumours with recently developed digitally-guided transducers of 5 and 7.5 MHz, we found that diagnosis and assessment are significantly facilitated by flexible endosonography. The demonstration of T1- and T2-tumours was shown to be facilitated by this technique as compared to other imaging methods. The assessment of large tumours is improved in special areas. Nonetheless, we recommend that in such cases flexible endosonography be supported by CT or MRI for a complete demonstration of the extent of the tumour.

Assessment of tumorous mandibular involvement by transcutaneous ultrasound and flexible endosonography.

Tumorous involvement of the mandible affects the prognosis and choice of treatment. To evaluate the usefulness of transcutaneous ultrasound and recently-developed flexible endosonography and their ability to display bone invasion in the lower jaw, we studied 33 non-selected patients with extensive, histologically-verified oral and oropharyngeal carcinomas. Both sonographic examinations were performed prospectively in all patients prior to surgery, without knowledge to the sonographer of the results of other imaging methods. Histological findings served as gold standards and offered 14 mandibular involvements. Flexible endosonography is characterized by high accuracy data in assessment of mandibular involvement occurring in tumors of the floor of the mouth and of the tonsil. On the other hand acceptable results by transcutaneous ultrasound could only be obtained in assessing bone invasion of oral tumors. However, osseous destruction in patients with oropharyngeal tumors were not detectable as the involved medial surface of the mandibular ramus was inaccessible to the extraorally placed transducer. Both sonographic methods, especially endosonography, enabled the examiner to differentiate cortical bone as opposed to spongiosa involvement in many cases, but failed in assessment of tumorous periosteal involvement. Pitfalls in detection and differentiation of bone invasion with false positive and false negative findings are discussed with regard to mandibular anatomy, for both intra- and extraoral examination.

Evaluation of pedicled skin flap viability by pH, temperature and fluorescein: an experimental study.

In order to test methods of predicting skin flap viability, a skin flap model in Sprague-Dawley rats was established. As criteria for studying skin flap survival, we compared measurement of skin pH, temperature, as well as fluorescence photography and computer aided digital morphometry (CADM). Ninety male Sprague-Dawley rats were divided into three groups in which pedicles were clamped for 10, 15, or 20 h. A standardized bipedicled skin flap was prepared, maintained by the epigastric artery, vein and nerve. All flaps were sutured back in place immediately after clamping. We found that postoperative prediction of flap survival based solely upon external appearance was impossible until the 2nd postoperative day. Changes in pH were not statistically significant in the prediction of vital or necrotic flaps. The temperature measurements showed, that in the event of viability the decrease in flap temperature versus the reference temperature (rectal temperature) was significant (P < 0.0094 in Group II, 15 h of ischaemia) or at least a tendency to significance (P < 0.059 in Group III, 10 h of ischaemia) bigger than in the event of partial or total flap necrosis. The photographic documentation using fluorescein showed that all coloured areas survived. Group I (20 h) showed predominantly total flap necrosis. Most flaps in Group III (10 h) exhibited a small necrotic area at the tip. In Group II (15 h) no typical staining pattern could be observed. Furthermore, computer aided digital morphometry demonstrated a decrease of the necrotic area by 7% between the 2nd and 4th postoperative day in Groups II and III. The method which gave the most exact prediction about viability was the fluorescein staining of the flaps via the tail vein.

Pediatric middle ear infections and gastroesophageal reflux.

OBJECTIVES: The pathogenesis of middle ear infections in children is multifactorial and includes infection, anatomical factors, impaired immunologic status, allergy, familial predisposition, male sex, method of feeding and environmental factors. Glue ear remains the commonest cause of deafness in childhood. Gastroesophageal reflux (GOR) 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. METHODS: We review the literature and discuss the possible relationship between Gastroesophageal reflux and otitis media in children. CONCLUSIONS: The current data are not enough to support antireflux treatment in children with refractory middle ear infections. More prospective randomised placebo-controlled studies are needed.

Dual-probe 24-hour ambulatory pH monitoring for diagnosis of laryngopharyngeal reflux.

BACKGROUND: Patients with gastroesophageal reflux disease may suffer from a variety of symptoms from the upper aerodigestive tract. The objective of this study was to determine the impact of dual-probe 24-hr pH monitoring in the diagnosis of reflux-related otolaryngological disorders. METHODS: Twenty-two patients with symptoms such as chronic cough, globus pharyngeus, heartburn, dysphonia and burning sensation of the tongue underwent a complete ear, nose and throat examination, 24-hr dual-probe pH monitoring, and oesophago-gastro-duodenoscopy. RESULTS: pH monitoring revealed gastroesophageal (distal) reflux in all patients and pharyngeal (proximal) reflux in 21 patients. Treatment consisted of a proton pump inhibitor (esomeprazole). Within 4 weeks 68 per cent of patients had no laryngopharyngeal symptoms; within 8 weeks 95 per cent of patients were symptom-free. CONCLUSIONS: Patients with atypical reflux symptoms such as hoarseness, globus sensation or throat-clearing responded well to anti-reflux treatment.

[Respiratory manifestations of reflux disease. Gastric acidity--poison for larynx, teeth and respiratory tract]. / Respiratorische Manifestationen der Refluxkrankheit. Der saure Magensaft--Gift für Kehlkopf, Zähne und Atemwege.

Gastroesophageal reflux is now a generally accepted risk factor for the development of adenocarcinoma of the esophagus. Less well known is the relationship of reflux disease (GERD) and respiratory disorders. Among the extra-esophageal manifestations of reflux disease is reflux laryngitis, which affects up to 78 patients with chronic hoarseness, Reinke's edema, laryngeal stricture, postnasal drip, asthma and non-cardiac chest pain. Despite popular opinion, changes in lifestyle (for example, cessation of smoking and drinking, avoidance of fatty foods) do not result in an improvement in symptoms. The treatment of choice for GERD is the use of proton pump inhibitors (PPI) in the form of stepdown therapy; in individual cases as symptom-orientated on-demand therapy.

Management of globus pharyngeus.

Globus pharyngeus is a common ENT condition. This paper reviews the current evidence on globus and gives a rational guide to the management of patients with globus. The aetiology of globus is still unclear though most ENT surgeons believe that reflux whether acidic or not plays a significant role. Though proton pump inhibitors are used extensively in practice, there is little evidence to support their efficacy. Most patients with globus can be discharged after simple office investigations. The role of pepsin-induced laryngeal injury is an exciting concept that needs further study. Given the benign nature of globus pharyngeus, in most cases, reassurance rather than treatment or extensive investigation with rigid oesophagoscopy or contrast swallows is all that is needed. We need more research into the aetiology of globus.

Laryngeal schwannoma: case report and literature review.

Neurogenic tumours of the larynx, particularly schwannomas are rare. We report a case report of a schwannoma in a 30-year-old woman which was excised endoscopically. The aim of this paper is to highlight this rare condition and management options to the otolaryngological community.