Prognostic factors for survival after salvage total laryngectomy following radiotherapy or chemoradiation failure: a 10-year retrospective longitudinal study in eastern Denmark.

OBJECTIVE: The primary aims were to determine the rates of and prognostic factors for overall survival, disease-specific survival and disease-free survival following salvage total laryngectomy. DESIGN: Retrospective longitudinal study. SETTING: Tertiary medical centres. PARTICIPANTS: A total of 142 patients in eastern Denmark undergoing salvage total laryngectomy for squamous cell carcinoma of the larynx or hypopharynx. MAIN OUTCOME MEASURES: 5-year overall survival, 5-year disease-specific survival, 5-year disease-free survival and prognostic factors for these outcomes. RESULTS: 5-year overall survival, disease-specific survival and disease-free survival were 37.7%, 54.9% and 55.3%, respectively. N classification at primary diagnosis, lymph node excision and postoperative complications within 1 year after salvage total laryngectomy were prognostic factors for shorter overall survival, disease-specific survival and disease-free survival. Residual tumour/recurrence was negatively associated with overall survival, close or involved resection margins with disease-specific survival, and second primary cancer was associated with longer disease-specific survival and disease-free survival. Nine per cent of all patients had residual tumour and 33.8% developed a recurrence. CONCLUSION: Our overall survival, disease-specific survival and disease-free survival findings are in accordance with previous studies. With the purpose of identifying recurrent tumour, we suggest extra attention being given to patients with higher N classification and need for lymph node excision during salvage total laryngectomy along with use of frozen sections. The high number of patients with recurrence within 1 year after salvage total laryngectomy occurred although thorough and regular follow-up visits were performed.

Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

Risk factors for postoperative complications after total laryngectomy following radiotherapy or chemoradiation: a 10-year retrospective longitudinal study in Eastern Denmark.

OBJECTIVES: To determine the rates of and risk factors for postoperative complications following total laryngectomy in patients treated with radiotherapy or chemoradiation. DESIGN: Retrospective longitudinal study. SETTING: Tertiary medical centres. PARTICIPANTS: A total of 143 patients undergoing total laryngectomy for squamous cell carcinoma of the larynx or hypopharynx. MAIN OUTCOME MEASURES: Overall postoperative complications and fistula formation. RESULTS: Overall postoperative complications, fistula formation, wound infection, bleeding and wound necrosis within one year after total laryngectomy occurred in 56.6%, 42.3%, 31.0%, 11.3% and 9.2% of patients, respectively. Stenosis of the pharynx/oesophagus and stoma shrinkage within five years after surgery were each seen in 18.2% of cases. In 66.7% of cases, conservative treatment of the fistulas was chosen. Rehospitalisations within five years occurred for 44.8% with a median rate of 1.5 (range 1-11). Smoking status (P = 0.005 and 0.013) and chronic obstructive pulmonary disease (COPD) (P = 0.013 and 0.011) were significant risk factors for both overall postoperative complications and fistula formation in uni- and multivariate analysis. Tumour localisation in the hypopharynx was associated with overall postoperative complications (P = 0.036). Residual tumour or cancer recurrence was associated with late-onset fistulas (P < 0.001). CONCLUSION: The frequencies of postoperative complications after total laryngectomy were comparable with similar international studies, although fistula formation rate is increasing in Denmark. We suggest optimising treatment of COPD and to further encourage to smoking cessation. We propose that development of fistulas >2 months after surgery prompts immediate biopsies. Additionally, we suggest standardised registration of surgical techniques to identify variables affecting the frequency of postoperative complications.

Mucosal immunity and bacteriology of the eustachian tube.

The pathogenesis of otitis media is a multifaceted process that is not completely understood. Eustachian tube dysfunction plays a central but uncertain role, as do viral and bacterial microorganisms. Of the latter, the three most important are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. This article reviews the various mechanisms of infection and the immune system's response to them.

Ribotyping of strains of Moraxella (Branhamella) catarrhalis cultured from the nasopharynx and middle ear of children with otitis media.

Moraxella (Branhaomella) catarrhalis is frequently present in the nasopharyngeal microflora of small children, especially during episodes of acute otitis media . By means of ribotyping (restriction endonuclease analysis of chromosomal DNA combined with rRNA probing), we studied the genetic heterogeneity of 78 cultures of M. catarrhalis obtained from different localities in the nasopharynx of nine young children with secretory otitis media. Using HindIII and PstI as endonucleases, five different ribotypes were recognized, representing at least five different genotypes of M. catarrhalis. The distribution of these types was found to be almost identical to the distribution among 16 M. catarrhalis strains cultured from middle ear exudates of 16 children with acute otitis media. Ribotype HAPA was found in two-thirds of all the cultures investigated, and 44% of the children harboured more than one ribotype in the nasopharynx at the same time. The vast majority of the nasopharyngeal M. catarrhalis cultures were beta-lactamase positive. One child had both a HAPA ribotype, beta-lactamase-negative strain in the nasopharyngeal secretions, and HAPA ribotype, beta-lactamase-positive strains at the entrance of the eustachian tube, the nasopharyngeal tonsils, the folds of the nasopharyngeal tonsils and the oropharynx. All except one of the M. catarrhalis strains cultured from middle ear exudates were beta-lactamase positive.

Mannan-binding protein--levels in plasma and upper-airways secretions and frequency of genotypes in children with recurrence of otitis media.

We have investigated a possible association between recurrence of otitis media and low concentrations of mannan-binding protein (MBP) in plasma and upper-airway secretions. The protein concentration was measured in plasma (n = 76), nasopharyngeal secretions (n = 83) and middle ear effusions (n = 73) from otitis-prone children, children with less recurrence of acute otitis media, children with no previous history of acute otitis media, but suffering from secretory otitis media, and healthy children. Moreover, genetic polymorphisms associated with low MBP plasma levels were investigated in DNA from nasopharyngeal tonsils of 89 children with recurrence of otitis media. A wide range of MBP plasma concentrations was found. No statistically significant differences in MBP plasma concentration were observed between patients and controls. Nor was there any increased frequency of the genotypes associated with low MBP plasma concentrations. Thus, our results do not support the assumption that low concentration and/or MBP deficiency alone predispose to recurrence of otitis media in Caucasian children. MBP was detected in both nasopharyngeal secretions (1/175 of plasma level) and middle ear effusions (1/4 of plasma level), suggesting a role for the protein in the local mucosal immune defense system at these locations. In contrast, MBP was undetectable in 53 samples of mixed-saliva.

Mucosal immunity to Pseudomonas aeruginosa alginate in cystic fibrosis.

Patients with cystic fibrosis commonly acquire chronic pulmonary infection with alginate-producing Pseudomonas aeruginosa. The infection remains localized at the mucosal surfaces of the airways. Using enzyme-linked immunosorbent assays immunoglobulin concentrations and titers of specific antibodies to purified P. aeruginosa alginate and to P. aeruginosa sonicated antigens were measured in tears, saliva, sputum and serum. CF patients had significantly higher concentrations of IgG, IgA and SIgA in serum and saliva than controls. They also had significantly higher levels of specific antibodies to alginate and sonicated antigen in secretions and serum. Local production of IgA, IgG and IgM antibodies to P. aeruginosa was demonstrated. Only a minor proportion of specific IgA antibodies were present as secretory IgA in tears, saliva and sputum. The ratio of alginate-specific SIgA to specific monomeric IgA in sputum was significantly lower than the similar ratio in saliva, whereas the same ratio for specific P. aeruginosa sonicate antigens was found in saliva and sputum.

Association between keratin staining patterns and the structural and functional aspects of palatine tonsil epithelium.

The keratin composition of stratified squamous epithelia has a complex pattern, which varies in different regions and as a result of pathological developments. The exact factors responsible for the characteristic keratin composition in a given epithelium are unknown. However, the environment, including factors from the connective tissue, is known to influence epithelial morphology and keratin composition. We here report that the reticulated squamous epithelium of the crypts of palatine tonsils shows an extensive staining for keratins 5 and 19 in basal as well as suprabasal cells, in contrast to neighbouring non-reticulated crypt epithelium and the epithelium at the tonsillar surface, in which staining is restricted to basal cells. The reticulation of the crypt epithelium is thought to be initiated by infiltration of immune-related cells in a preexistent non-reticulated epithelium. The extensive staining for keratins 5 and 19 in reticulated crypt epithelium correlates with the presence of numerous immune system-related cells and marked expression of intercellular adhesion molecule-1 (ICAM-1), thought to be involved in inflammatory and immunological responses. The results suggest that the massive lymphocytic traffic in the reticulated crypt epithelium and the overall distinct immune environment are responsible for the unique keratin staining pattern observed.

Local production of IgG to pneumococcal C-polysaccharide in upper airway secretions from children with recurrent acute otitis media.

Antibodies against C-polysaccharide (C-Ps), a common cell wall component of all pneumococci, may be of importance for the elimination of decaying pneumococci. By means of ELISA with phenylated C-Ps, anti-C-Ps IgG was measured in samples of plasma and upper airway secretions from otitis-prone children (OP), children with fewer episodes of recurrent acute otitis media (rAOM), and children with no previous history of AOM, but suffering from secretory otitis media (SOM). All children were free from acute illness at the time of sampling. No statistically significant differences of anti-C-Ps IgG in plasma or in nasopharyngeal secretions (NPS) were found between any of the groups. Based on calculations of the correlation between levels of anti-C-Ps IgG in plasma and NPS, and of the transudation ratios of anti-C-Ps IgG, total IgG, and albumin from plasma to NPS, we suggest that a significant amount of the anti-C-Ps IgG in NPS must be locally produced. The additional finding that OP children had significantly higher levels of anti-C-Ps IgG in their middle ear effusions (MEE) than SOM children points in the same direction. Anti-C-Ps IgA and IgM were detected in very low concentrations in plasma and secretion samples.

Concentrations of IgA, secretory IgA, IgM, secretory IgM, IgD, and IgG in the upper jejunum of children without gastrointestinal disorders.

Jejunal fluid was collected from 40 children aged 1-12.2 years and from 10 adults (age 20-25 years) who were without gastrointestinal disorders. They were intubated pernasally with a special tube system that made it possible to avoid contamination from the upper respiratory tract secretions. Quantitation of immunoglobulin A (IgA), secretory IgA (SIgA), IgM, SIgM, IgD, IgG, and albumin was performed by double sandwich enzyme-linked immunosorbent assay. IgA was the dominating immunoglobulin in jejunal fluid, showing the highest concentrations, followed in order by IgM, IgG, and IgD. The IgD concentrations were about 1,000 times less than in plasma of age-matched children. The immunoglobulin concentrations did not show any age-related differences, except for IgG and for the SIgA/IgA ratio. The former declined with children's age (p less than 0.02), whereas the latter was significantly higher in adults (interquartile range: 97-100%) than in young children aged 1-less than 5.5 years (interquartile range: 55-94%) (p less than 0.001). This indicates an age-related decline in leaking from gut mucosa. The concentrations of SIgA and SIgM showed a positive correlation (p less than 0.001). The majority of IgA and IgM were estimated to be locally produced, whereas IgD and IgG were transudated from plasma.

Plasma IgG, IgG subclasses and acute-phase proteins in children with recurrent acute otitis media.

Quantitation of IgG, IgG subclasses and acute-phase proteins was performed in plasma samples from 156 children, aged 2 to 162 months, with varying degrees of otitis proneness. None of the children had acute otitis media or had received any antibiotics 3 weeks before the examination. Children with recurrent acute otitis media (rAOM) had significantly higher levels of total IgG, IgG1, and significantly lower levels of IgG2 than healthy children (p less than 0.02, p less than 0.0003, and p less than 0.03, respectively). However, the low levels of IgG2 found in the rAOM children could at least, to some extent, be explained by the observation that these children were somewhat younger than the healthy children. Except for recurrent episodes of common colds, children suffering from secretory otitis media (SOM) most often show no clinical signs of inflammatory events. Nevertheless, children with SOM had raised levels of plasma IgG1, indicating recurrent polyclonal stimulation of the immune apparatus, which seems to be less pronounced than that of rAOM children. Levels of acute-phase proteins, haptoglobin, orosomucoid and alpha 1-antitrypsin were evenly distributed in the children investigated, reflecting that they had no acute illness at the time of plasma sampling.

IgD in nasopharyngeal secretions and tonsils from otitis-prone children.

Quantification of IgD was performed by ELISA in 180 plasma samples and 83 nasopharyngeal secretions (NPS) from children aged 2-162 months with varying degrees of recurrent otitis media. Furthermore, in 24 of the children the density of the IgD-immunocytes (IgD-cells) was calculated in immunoenzyme-stained cross-sections of their nasopharyngeal tonsils (NPT). Owing to a considerable variation of the IgD cell density throughout the NPT, a semi-quantitative counting system was applied. An irregular distribution of plasma IgD was observed during childhood and maximum levels were found between 48 and 72 months of age. However, an even distribution of plasma IgD was found among the four groups of children investigated. Based on calculations of the transudation of albumin from plasma to the NPS the amount of locally produced IgD in NPS (NPS-IgD (local] was estimated to 88% (range 41-99%). Significantly higher levels of NPS-IgD (local) were found in otitis-prone children than in the other groups. Moreover, a positive correlation was calculated between levels of NPS-IgD (local) and NPT-IgD cell density, indicating that NPT, being the local lymphoepithelial tissue, also functions as an important source of NPS-IgD. NPS-IgD was not found to be associated with secretory component, indicating a passive transfer of IgD through the mucosal membranes. Our results support the hypothesis of an association between the occurrence of IgD in the mucosa and secretions of the upper respiratory tract with localized inflammatory events.

Nasopharyngeal secretory immunoglobulins in children with recurrent acute otitis media and secretory otitis media.

Secretory IgA (SIgA) and secretory IgM (SIgM), total IgA and total IgM were measured in plasma and nasopharyngeal secretions (NPS) from young children with different degrees of otitis proneness. Significantly higher levels of plasma IgM and lower levels of NPS-SIgM were found in children with recurrent episodes of acute otitis media (rAOM) compared with children suffering from secretory otitis media (SOM) and healthy controls. Both plasma IgA and NPS-SIgA were evenly distributed in the three groups of children investigated, and in most children the levels of NPS-SIgA exceeded plasma IgA levels. Plasma SIgA was significantly increased in children with rAOM and SOM, probably resulting from frequent occurrence of inflammatory events at the nasopharyngeal level. No correlation could be demonstrated between NPS-SIgA and plasma IgA, or between NPS-SIgM and plasma IgM. Also, for both NPS-SIgA and NPS-SIgM, there was no correlation with age. A negative correlation was observed between the transudation index of albumin to the nasopharynx and the ratio of NPS-SIgA to total NPS-IgA. A ratio of 1 (100%) corresponded to a transudation index of 8%. The ratios of NPS-SIgA to total NPS-IgA varied considerably and a range of 39%-88% could only to some extent be explained by transudation of plasma IgA to NPS. The results of the present study show that the children with rAOM and SOM are well furnished with locally produced SIgA antibodies at the nasopharyngeal level. In children with SOM, the nasopharyngeal hypofunction in the case of low NPS-SIgM seems to be less pronounced compared with that of otitis-prone children.

Nasopharyngeal bacteriology and secretory otitis media in young children.

A prevalence study was performed on the nasopharyngeal bacteriology of 112 young children, aged 4-6 years. During the preceding 2 years, 74 of these children had suffered from secretory otitis media (SOM) and 40 had had normal middle ear ventilation. At the examination, one-third of the children with SOM had improved their middle ear status (previous SOM group), whereas otomicroscopy and tympanometry remained unchanged in the healthy group. The nasopharyngeal swab sample was obtained from behind the soft palate by the oral route. The isolation rate of Streptococcus pneumoniae was significantly higher in the SOM group than in the two other groups of children (p less than 0.006). The most commonly isolated capsular types of pneumococci were 6, 19, and 23, corresponding to the types involved in acute otitis media. The isolation rate of Haemophilus influenzae was 50% and an even distribution was found among the three groups of children examined. Biotypes I, II, III and IV accounted for 75% of the isolated cases of H. influenzae. As in acute otitis media, S. pneumoniae also seemed to play an important role in the pathogenesis of tubal dysfunction and SOM, and the difference is probably caused by variations in the quantitative colonization of pneumococci in the nasopharynx.

Influence of antibiotic treatment on the isolation rate of group A streptococci from peritonsillar abscesses.

In a prospective one-year study, group A streptococci were cultured from pus specimens from 13 of 71 patients (18%) with peritonsillar abscesses. The isolation rate was significantly lower (7/57 = 12%) in patients who had received antibiotic treatment before specimen collection than in patients who had not received such treatment (6/12 = 50%). Group A streptococcus antigen detection tests on pus, using a commercially available diagnostic kit, had a low sensitivity (5/13 = 38%). It was concluded that in patients treated with antibiotics prior to collection of specimens, the absence of group A streptococcus on culture does not rule out that this organism could have been the principal etiologic agent.

Biochemical analysis of nasal secretions induced by methacholine, histamine, and allergen provocations.

Nasal provocation tests with methacholine, histamine, and allergen were performed outside the pollen season in 26 pollen-allergic subjects with the aim of sampling nasal secretions for biochemical characterization. Sugar analyses showed that methacholine-induced secretions were a mixture of serous and mucous glycoproteins. Compared with published sputum values, the levels of proteins and sugars were approximately 5 times lower in the methacholine-induced secretions (protein, 6 mg/ml; hexose, 2 mg/ml), whereas the albumin concentrations were comparable (1 mg/ml). Histamine-induced secretions as well contained a mixture of serous and mucous glycoproteins and a high albumin level (3 mg/ml), indicating a relatively higher degree of transudation than in methacholine- and allergen-induced secretions. Allergen-induced secretions had a low dry weight (mean, 19 mg/g; p less than 0.05) and protein (mean, 4 mg/ml; p less than 0.01) content compared with that in methacholine- and histamine-induced secretions; they contained mainly mucous glycoprotein, and the albumin level was relatively low. Thus, nasal secretions have lower dry weight, sugar and protein content than does sputum; histamine provokes marked transudation; methacholine and allergen do not; methacholine and histamine produce a mixture of serous and mucous glycoproteins; allergen produces mainly mucous glycoproteins.

Spontaneous course of secretory otitis and changes of the eardrum.

In 222 nonselected, otherwise healthy children, seven repetitive tympanometric screenings were performed from ages 4 to 7 years. At the last three screenings, otomicroscopy was performed and the changes of the eardrum were analyzed. At age five years 24%, at age six years 37%, and at age seven years 39% of all 444 ears had changes of the eardrum, either attic retractions of varying degrees, atrophy, and/or tympanosclerosis of the pars tensa. There was a notable correlation between eardrum abnormality, the tympanometric profile, and the frequency of acute otitis media. Some unstability of the eardrum abnormality occurred over the years, especially of attic retractions and tympanosclerosis. Treatment, especially by grommets, probably cannot prevent eardrum abnormality.

Bacterium-induced cleavage of IgA in nasopharyngeal secretions from atopic children.

Immunoglobulin A forms the specific immune barrier of mucosal surfaces against microorganisms and potential allergens. Immunochemical studies of nasopharyngeal secretions (NPS) from 97 children showed enzymatic degradation of IgA in 18.6% of the samples. The observed fragments are characteristically released from IgA by the activity of specific IgA 1 proteases produced by certain bacterial species. A significantly higher prevalence (P less than 0.001) of IgA cleavage was observed in NPS from children with atopic diseases (61.5%) than in controls (11.9%). These results indicate that bacterium-induced local defects in the mucosal immune barrier of the upper respiratory tract may be a factor in the pathogenesis of some forms of atopic disease.