Treatment and survival of patients with non-small cell lung cancer Stage IIIA diagnosed in 1989-1994: a study in the region of the Comprehensive Cancer Centre East, The Netherlands.

The purpose of this study was to gain insight into the treatment policy and survival of patients with non-small cell lung cancer (NSCLC) clinical stage IIIA in daily practice. We selected 212 patients, who had been diagnosed between 1989 and 1994 and registered by the Cancer Registry, Comprehensive Cancer Centre East (CCCE). Diagnostic tests comprised chest X-ray and bronchoscopy in all cases but one, computed tomography in 89%, mediastinoscopy in 55% and conventional tomography of the chest in 16%. NSCLC had been verified histologically in 88% and cytologically in 12%. The initial treatment for the primary tumor had been surgery alone in 13% of the patients, surgery plus radiotherapy in 8%, radiotherapy alone in 56%, chemotherapy in 1% (three patients, one in addition to surgery); 22% received none of these treatments. Median survival of the 212 patients was 9.4 months (95% confidence interval 8.3-11.0 months). Overall survival rates after 1, 2 and 3 years were 41, 17 and 8%, respectively. Three-year survival of the patients who had undergone surgery, surgery plus radiotherapy, radiotherapy alone and no treatment was 18, 19, 6 and 4%, respectively. Treatment was an independent prognostic factor (multivariate Cox's proportional hazards analysis adjusted for sub-stage, age, number of co-morbid diseases and hospital). In the same model, the Hazard rate ratio for one hospital relative to the five others was 1.9 (95% confidence interval 1.2-2.8). Surgery (whether or not in combination with radiotherapy) independently gave the best results. In conclusion, policies varied between hospitals, although the variation in overall survival was small except at one hospital. New regional management guidelines are in preparation. Physicians will be encouraged to follow these guidelines, both with regard to diagnostic tests and to treatment policies, as our study showed that differences in policy might lead to differences in survival.

Effects of single-dose zileuton on bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids.

The aim of the study was to determine whether zileuton, an inhibitor of 5-lipoxygenase, attenuated bronchial hyperresponsiveness (BHR) in asthmatic subjects who had marked BHR during maintenance treatment with inhaled corticosteroids (ICS). In a randomized, double-blind, placebo-controlled, cross-over study, a challenge test with histamine (provocative concentration of histamine producing a 20% fall in forced expiratory volume in one second (FEV1) (PC20,Hist)) and with ultrasonically nebulized distilled water (UNDW) (provocative dose of UNDW producing a 20% fall in FEV1 (PD20,UNDW)) was performed in seven patients with asthma after intake of either 400 mg zileuton or placebo. All patients (mean age 33 yrs, mean FEV1 111% of predicted) had marked BHR, as indicated by a mean PD20,UNDW of 4.74 mL under treatment for at least 6 months with up to 800 microg ICS (mean 536 microg daily). On four different occasions, separated by at least 5 days, two UNDW and two histamine challenge tests were performed in random order 3 h after a morning dose of either zileuton or placebo. Neither zileuton nor placebo changed baseline airway calibre prior to provocation. Zileuton increased PC20,Hist from 0.99 to 5.64 mg x mL(-1) (2.1 doubling doses; p<0.03 compared to placebo), and increased PD20,UNDW from 3.10 to 9.31 mL (1.3 doubling doses; p<0.05 compared to placebo). In conclusion, a single dose of 400 mg zileuton attenuates bronchial hyperresponsiveness to histamine and ultrasonically nebulized distilled water in asthmatic patients with marked bronchial hyperresponsiveness during treatment with inhaled corticosteroids.

Effect of reducing slow temporal modulations on speech reception.

The effect of reducing low-frequency modulations in the temporal envelope on the speech-reception threshold (SRT) for sentences in noise and on phoneme identification was investigated. For this purpose, speech was split up into a series of frequency bands (1/4, 1/2, or 1 oct wide) and the amplitude envelope for each band was high-pass filtered at cutoff frequencies of 1, 2, 4, 8, 16, 32, 64, or 128 Hz, or infinity (completely flattened). Results for 42 normal-hearing listeners show: (1) A clear reduction in sentence intelligibility with narrow-band processing for cutoff frequencies above 64 Hz; and (2) no reduction of sentence intelligibility when only amplitude variations below 4 Hz are reduced. Based on the modulation transfer function of some conditions, it is concluded that fast multichannel dynamic compression leads to an insignificant change in masked SRT. Combining these results with previous data on low-pass envelope filtering (temporal smearing) [Drullman et al., J. Acoust. Soc. Am. 95, 1053-1064 (1994)] shows that at 8-10 Hz the temporal modulation spectrum is divided into two equally important parts. Vowel and consonant identification with nonsense syllables were studied for cutoff frequencies of 2, 8, 32, 128 Hz, and infinity, processed in 1/4-oct bands. Results for 12 subjects indicate that, just as for low-pass envelope filtering, consonants are more affected than vowels. Errors in vowel identification mainly consist of reduced recognition of diphthongs and of durational confusions. For the consonants there are no clear confusion patterns, but stops appear to suffer least. In most cases, the responses tend to fall into the correct category (stop, fricative, or vowel-like).

The protective effects of ipratropium bromide and terbutaline on distilled water-induced bronchoconstriction.

In a randomized, double-blind, placebo-controlled study, we investigated the protective effects of ipratropium bromide 160 micrograms and 320 micrograms and terbutaline 500 micrograms on ultrasonically nebulized distilled water (UNDW)-induced bronchoconstriction in nine stable asthmatic patients. Both drugs caused a significant increase (P < 0.001) in baseline FEV1 with no significant differences between the drugs or both doses of ipratropium bromide. Pre-inhalation of ipratropium bromide 320 micrograms and terbutaline 500 micrograms inhibited UNDW-induced bronchoconstriction (P < 0.01), whereas ipratropium bromide 160 micrograms had no protective effect. The protective effects of ipratropium bromide showed a large interindividual variation. There was no correlation between the increase in baseline FEV1 and PD20 UNDW, indicating that the protective effect on UNDW-induced bronchoconstriction is not dependent on the bronchodilation induced by terbutaline and ipratropium bromide. It also appears that the UNDW-induced bronchoconstriction is at least partly vagally mediated.

Effect of temporal envelope smearing on speech reception.

The effect of smearing the temporal envelope on the speech-reception threshold (SRT) for sentences in noise and on phoneme identification was investigated for normal-hearing listeners. For this purpose, the speech signal was split up into a series of frequency bands (width of 1/4, 1/2, or 1 oct) and the amplitude envelope for each band was low-pass filtered at cutoff frequencies of 0, 1/2, 1, 2, 4, 8, 16, 32, or 64 Hz. Results for 36 subjects show (1) a severe reduction in sentence intelligibility for narrow processing bands at low cutoff frequencies (0-2 Hz); and (2) a marginal contribution of modulation frequencies above 16 Hz to the intelligibility of sentences (provided that lower modulation frequencies are completely present). For cutoff frequencies above 4 Hz, the SRT appears to be independent of the frequency bandwidth upon which envelope filtering takes place. Vowel and consonant identification with nonsense syllables were studied for cutoff frequencies of 0, 2, 4, 8, or 16 Hz in 1/4-oct bands. Results for 24 subjects indicate that consonants are more affected than vowels. Errors in vowel identification mainly consist of reduced recognition of diphthongs and of confusions between long and short vowels. In case of consonant recognition, stops appear to suffer most, with confusion patterns depending on the position in the syllable (initial, medial, or final).

Contributions of comodulation masking release and temporal resolution to the speech-reception threshold masked by an interfering voice.

Two experiments are presented to explain the difference in speech-reception threshold (SRT) between conditions with a steady-state noise masker or an interfering voice. Literature shows for normal hearing a masking release of 6-8 dB with an interfering voice and a substantial reduction of this release with hearing impairment. In experiment I the possible role of comodulation masking release (CMR) is investigated by manipulating the comodulation in the interfering voice by the introduction of temporal shift among filter bands of various width. The spectral spread of masking from the manipulated interfering voice was controlled by interleaving the mutually shifted speech bands with 1/3-octave bands of noise. Although comodulation in the interfering speech appears to be very important for the low SRT, the contribution of across-frequency processing of masker fluctuations--commonly considered as the origin of CMR--is only 1.3 dB. In experiment II the level dependence of masking release with an interfering voice is investigated. The data fit in with the hypothesis by Festen and Plomp [J. Acoust. Soc. Am. 88, 1725-1736 (1990)] that the release from masking with an interfering voice is limited by forward masking. It appears that up to about 55 dBA the release from masking increases with level up to about 7 dB. Above 55 dBA the difference in SRT obtained with a noise masker or an interfering voice is constant due to the limited average modulation depth of speech.

The efficacy of a multichannel hearing aid in which the gain is controlled by the minima in the temporal signal envelope.

A multichannel signal-processing hearing aid in which the gain is controlled by the level of the minima in the sound envelope [outlined by Festen et al., 1990] was evaluated with hearing-impaired listeners. This evaluation is an extension to the work reported by van Dijkhuizen et al. (1990). A first experiment focused on the speech-reception threshold (SRT), i.e. the S/N ratio for 50% intelligibility. The greatest benefit in terms of the SRT from frequency-dependent control of the amplification is expected in conditions where the spectrum of noise exceeds strongly that of the speech in a limited frequency region. In these conditions frequency-dependent amplification may reduce upward spread of masking. We investigated the upper limit of this benefit in conditions of intense frequency-limited interfering noise. Speech and noise were both spectrally shaped according to the line bisecting the listener's dynamic range; however, the level of the noise in one octave band (0.25-0.5 or 0.5-1 kHz) was increased by 20 dB. The results show that frequency-selective attenuation of the signal in the octave band with the 20-dB increase of noise is more beneficial than wide-band gain control, and gives a decrease in SRT of up to 4 dB relative to a condition without gain control. In a subsequent experiment we investigated, for several very common interfering sounds, the effect of controlling the gain by the minima in the signal envelope on both the SRT and the perceived noisiness. Results show that the condition with gain control does not affect the SRT for sentences in the presence of everyday interfering sounds having spectra that are roughly comparable to that of the speech signal; however, it substantially reduces the perceived noisiness. In line with our expectations, the effect of the gain control on the signal was very small for a single voice, and it was greatest in case of sounds with a more or less continuous character (e.g. stationary noise, music). For these last sounds it was found that the growth in perceived noisiness with the increase of input level is equivalent to the growth produced by only about one-fifth of the increase in input level (in decibels) in a condition without gain control.

Effect of spectral envelope smearing on speech reception. I.

The effect of reduced spectral contrast on the speech-reception threshold (SRT) for sentences in noise and on phoneme identification, was investigated with 16 normal-hearing subjects. Signal processing was performed by smoothing the envelope of the squared short-time fast Fourier transform (FFT) by convolving it with a Gaussian-shaped filter, and overlapping additions to reconstruct a continuous signal. Spectral energy in the frequency region from 100 to 8000 Hz was smeared over bandwidths of 1/8, 1/4, 1/3, 1/2, 1, 2, and 4 oct for the SRT experiment. Vowel and consonant identification was studied for smearing bandwidths of 1/8, 1/2, and 2 oct. Results showed the SRT in noise to increase as the spectral energy was smeared over bandwidths exceeding the ear's critical bandwidth. Vowel identification suffered more from this type of processing than consonant identification. Vowels were primarily confused with the back vowels /c,u/, and consonants were confused where place of articulation is concerned.

Influence of antibiotics on IgA and IgG response and persistence of Yersinia enterocolitica in patients with Yersinia-associated spondylarthropathy.

The IgA and IgG antibody response to plasmid-encoded outer membrane proteins was studied in 59 patients with yersinia-associated spondylarthropathy during 15 months of follow-up. Initially, all patients had specific IgA and IgG antibodies to the 36 and 46 kDa and 30% also to the 26 and 58 kDa released proteins, which correlated with the finding of virulent Yersinia bacilli in intestinal biopsies. IgA disappeared in 69% of untreated patients after nine months and persisted in 31% after one year. IgA disappeared within three to six months in 81% of the patients treated with antibiotics for four to six weeks and persisted in 6% after one year (p less than 0.002). IgG antibodies to the 36 and 46 kDa outer membrane proteins persisted in 80% of all patients. Disappearance of IgA was coupled with disappearance of yersinia from intestinal biopsies.

Measurement of tracheobronchial clearance after sauna in subjects with chronic bronchitis.

The effect of sauna on tracheobronchial clearance was studied in five male patients with chronic bronchitis by a radioaerosol technique. No enhancement of tracheobronchial clearance could be detected.

Effect of positive expiratory pressure mask physiotherapy (PEP) versus forced expiration technique (FET/PD) on regional lung clearance in chronic bronchitics.

On theoretical grounds it is assumed that positive expiratory pressure mask physiotherapy (PEP) as a means of promoting mucus clearance is especially effective in the more distal airways. In a randomized cross-over trial including a control measurement the effect of PEP and of the forced expiration technique combined with postural drainage (FET/PD) on regional lung clearance was evaluated in seven patients with chronic bronchitis and abundant sputum production (mean 32 g.day-1). PEP consisted of positive expiratory pressure mask breathing interspersed with breathing exercises, forced expiration manoeuvres (huffing) and, if necessary, coughing. FET consisted of breathing exercises, huffing and also, if necessary, coughing. FET was combined with PD. Following inhalation of a radio-aerosol regional lung clearance was estimated by means of gamma camera imaging. The results after PEP appeared to be not significantly different from control. The mean clearance in all three lung zones (peripheral, intermediate and inner) was largest after FET/PD as compared with PEP and control. Statistical significance (p less than 0.02) was reached only for clearance in the inner region. It is concluded that PEP has no demonstrable effect on regional lung clearance in these patients.

No effect of oral high frequency oscillation combined with forced expiration manoeuvres on tracheobronchial clearance in chronic bronchitis.

This study compared the effect of oral high frequency oscillation (OHFO) with the effect of the forced expiration technique (FET) on tracheobronchial clearance. Eight patients with chronic bronchitis were investigated (mean age 60 +/- 10 yrs, mean forced expiratory volume in one second (FEV1) 68 +/- 27% predicted, mean sputum production 33 +/- 9 g.day-1). OHFO was applied at the respiratory system resonant frequency of each patient (range 9.2-25 Hz) and combined with huffing. FET included breathing exercises, huffing and postural drainage. Duration of both OHFO and FET was 30 minutes. Tracheobronchial clearance was measured by means of a radio-aerosol technique. At 60 mins after start of the treatment mean tracheobronchial retention was 70 +/- 26% after OHFO, 54 +/- 26% after FET and 76 +/- 18% in the control run, which included huffing only. OHFO was not significantly different from control. FET was significantly different (p less than 0.02) from both OHFO and control. It is concluded that OHFO has no effect on tracheobronchial clearance in chronic bronchitis.

The effect of positive expiratory pressure versus forced expiration technique on tracheobronchial clearance in chronic bronchitics.

In a randomized cross-over trial, including a control measurement the effect of positive expiratory pressure (PEP) and forced expiration technique (FET) on tracheobronchial clearance was evaluated in eight chronic bronchitics with abundant sputum production (mean, 32 g/day). PEP consisted of PEP-mask breathing interspersed with breathing exercises, huffing, and coughing. FET consisted of postural drainage, breathing exercises, huffing, and coughing. Clearance was measured with a radio-aerosol technique. At 40 min after the start of therapy the mean clearance, expressed as percentage of the amount of radioactivity present at the start of therapy, was 32% after PEP, 53% after FET, and 15% in the control run. The difference between PEP, FET, and control was statistically significant (p less than 0.02). Sputum production during PEP and FET was larger than during the equivalent period of time in the control run. It is concluded that FET is more effective than PEP in enhancing tracheobronchial clearance.

Relations between auditory functions in normal hearing.

The relations among a number of auditory functions were studied by concentration on small interindividual differences in these functions. For this purpose a battery of 12 tests was applied to 50 normal-hearing subjects. The tests included absolute threshold, auditory bandwidth measured with comb-filtered noise in direct and in forward masking, psychophysical tuning curve both in direct and in forward masking, temporal integration measured with intensity-modulated noise, forward- and backward-masking curves, cubic-difference-tone strength, and lateral suppression. In all cases the test frequency was 1000 Hz. Among the relations found, are (1) a positive correlation between the shift of the steep edge of the tuning curve, away from the probe frequency, and the width of the auditory filter as measured with comb-filtered noise, (2) an inverse relation between the width of the tuning curve and the width of the temporal window, and (3) a positive correlation between the width of the auditory filter and the strength of the cubic difference tone. Low correlations among tests were not caused by poor test reliability.