Akt phosphorylation on Thr308 but not on Ser473 correlates with Akt protein kinase activity in human non-small cell lung cancer.

BACKGROUND: The activity of the protein kinase Akt is frequently dysregulated in cancer and is an important factor in the growth and survival of tumour cells. Akt activation involves the phosphorylation of two residues: threonine 308 (Thr308) in the activation loop and serine 473 (Ser473) in the C-terminal hydrophobic motif. Phosphorylation of Ser473 has been extensively studied in tumour samples as a correlate for Akt activity, yet the phosphorylation of Thr308 or of downstream Akt substrates is rarely assessed. METHODS: The phosphorylation status of Thr308 and Ser473 was compared with that of three separate Akt substrates - PRAS40, TSC2 and TBC1D4 - in fresh frozen samples of early-stage human non-small cell lung cancer (NSCLC). RESULTS: Akt Thr308 phosphorylation correlated with the phosphorylation of each Akt substrate tested, whereas Akt Ser473 phosphorylation did not correlate with the phosphorylation of any of the substrates examined. CONCLUSION: The phosphorylation of Thr308 is a more reliable biomarker for the protein kinase activity of Akt in tumour samples than Ser473. Any evaluation of the link between Akt phosphorylation or activity in tumour samples and the prediction or prognosis of disease should, therefore, focus on measuring the phosphorylation of Akt on Thr308 and/or at least one downstream Akt substrate, rather than Akt Ser473 phosphorylation alone.

[Recommendations for training courses in bronchoscopy]. / Empfehlungen zu Trainingskursen in der Bronchoskopie.

Bronchoscopic training courses are an essential part of the education in bronchoscopy for all kinds of specialisations and professions performing such investigations. All aspects of the application should be mentioned during a course. These recommendations are necessary because the number of bronchoscopies performed in the last years has increased due to the increasing number of patients, improved equipment and better availability. Courses should provide the basic knowledge including main points of indications, preconditions for the procedure and decisions of consequence after bronchoscopy. Participants should be trained in the skills of correct handling and performing flexible bronchoscopies in training dummies. Necessary competence requirements on the course instructor are adequate professional qualifications, paedagogic skills and the availability of appropriate teaching material. Quality assurance of the course should be achieved by consequent evaluation. A widely spread field of bronchoscopic applications can improve patient care in many medical specialisations.

Fine-needle interstitial photodynamic therapy of the lung parenchyma: photosensitizer distribution and morphologic effects of treatment.

STUDY OBJECTIVE: To look at the effect of interstitial photodynamic therapy (PDT) in normal lung parenchyma to assess its potential for treating localized, peripheral lung tumors. DESIGN: Studies were performed on normal Wistar rats using the photosensitizer meso-tetrahydroxyphenyl chlorine. Drug distribution was measured by fluorescence microscopy on tissue sections. Light was delivered to the lungs via a single fiber inserted percutaneously under x-ray control and the PDT effect studied in animals killed at times up to 6 months later. RESULTS: Fluorescence studies showed that the drug was initially distributed throughout the lung, but was later predominantly in the vasculature, bronchi, and macrophages. PDT produced sharply defined zones of hemorrhagic necrosis up to 12 mm in diameter that healed with regeneration of bronchial epithelium and local fibrosis. Different histologic effects were seen between drug light intervals of 1 and 3 days. Treatment was well tolerated, there was a low incidence of pneumothorax, and as long as the fiber tip was within the lung parenchyma, there was no damage to adjacent tissues. CONCLUSION: Interstitial PDT produces zones of necrosis in normal lung that heal safely by a percutaneous technique without affecting adjacent areas of untreated lung. If the lesion size can be increased by using multiple fibers, this could be a promising new technique for treating localized, peripheral lung cancers in patients who are unfit for surgery.

The role of computed tomography (CT) in the investigation of unexplained haemoptysis.

Forty patients with a history of haemoptysis, normal chest radiographs apart from evidence of chronic airflow limitation, and normal fibreoptic bronchoscopy (or blood alone in the bronchial tree) were investigated by computed tomography (CT). Abnormalities were seen in 20 (50%) of the CT scans. Seven of the patients had evidence of bronchiectasis (18%), one of whom also had a mass. In four (10%) cases a mass alone was detected (two tuberculous, two malignant). In a further four (10%) scans alveolar consolidation was present and in three cases abnormal vessels were detected (7.5%). One patient had cystic changes shown in their scan and multiple nodules were shown in the final patient. The contralateral lungs of 93 patients undergoing CT for pre-operative assessment of bronchogenic carcinoma were used as controls. In six (6%) of these patients abnormalities were detected by CT. Pleural nodules were observed in two patients, fat in the transverse fissure in another, atelectasis in two patients and an apical bulla in the other abnormal scan. The relative risk for patients with unexplained haemoptysis having abnormal CT scans compared to the control group of patients was 7.75. We conclude that computed tomography is of value in the investigation of patients with unexplained haemoptysis.

Tracheal tumours: could treatment be better?

The rarity of primary tracheal tumours makes research into their natural history and treatment very difficult. Diagnosis is often made too late for cure. Palliation has improved with the introduction of laser resection, brachytherapy and stents. Squamous cell carcinoma may have a better prognosis in the trachea than in the lung. It has been assumed that surgery is the treatment of choice and up to 50% of the trachea can be resected with modern techniques. However, several of the largest surgical series have used mostly post-operative radiotherapy and really represent the results of combined therapy. High dose radiotherapy may achieve cure in some cases. Prospective studies of the relative merits of surgery and radiotherapy are urgently needed. The British Thoracic Society Research Committee is launching a national study at the present time.

Endoscopic applications of lasers in the bronchial tree.

Bronchial carcinoma causes some 30,000 deaths per year in the UK and only 10-20% of patients have any chance of surgical care. Radiotherapy and chemotherapy are mainly palliative treatments, yet they have considerable toxicity. In recent years laser bronchoscopy, with its advantages of speed, safety and freedom from toxicity, has proved a valuable addition to the established palliative therapy.

Primary tracheal tumours: a national survey.

BACKGROUND: Primary tracheal tumours are rare, so few physicians have extensive experience of their management. No direct comparisons have been made of surgical and radiotherapy treatment. METHODS: A postal survey of cases presenting in the last 10 years in the United Kingdom was conducted. Results were expressed as cumulative survival and survival curves were compared by the log rank test. RESULTS: Three hundred and twenty one patients were recruited. Overall five year survival rates were 25% for squamous cell carcinomas, and 80% for adenoid cystic carcinoma; 62% received radiotherapy but only 10% underwent surgery. Small cell carcinoma was more common than expected with an incidence of 6%. In patients with squamous carcinoma improved survival was seen in those with tumour in the upper trachea. High dose radiotherapy was more effective than low dose only in tumours of the upper trachea and in squamous carcinoma. In adenoid cystic carcinoma no significant difference in survival rate was seen between treatment with radiotherapy and surgery. No histological diagnosis was made in 44 patients, the most common reason being fear over the safety of fibreoptic bronchoscopy; however, this group had a cumulative survival at five years of 46%. CONCLUSIONS: Survival may be somewhat better in cases with tracheal tumours than in those with bronchial tumours. Small cell carcinoma is less rare than was previously thought. Upper tracheal tumours may merit more aggressive therapy. It is important to make a histological diagnosis even if rigid bronchoscopy is necessary, and referral to specialist centres is recommended. A larger prospective study is required to compare the value of surgery and radiotherapy.

Comparison of salbutamol Rotahaler with conventional pressurized aerosol.

Salbutamol in a powder aerosol from the Rotahaler insufflator was compared, with equal doses of the conventional pressurized aerosol by dose-response curves and in a 1 month open trial, in the treatment of asthma patients with good inhalation technique. Results were not significantly different in either study. A further group of asthma patients, who were known to be incapable of using pressurized aerosols effectively, were shown to benefit from treatment with the Rotahaler. This device should increase the value of the sympathomimetic drugs to the minority of asthma patients who cannot use conventional aerosols correctly.

Diurnal variation of asthma.

We have studied possible aetiological factors in the large diurnal variation in peak expiratory flow rate seen in some asthmatics. This phenomenon occurred in both atopic and non-atopic patients. It could not be attributed to recumbency in bed at night or to allergy to the house dust mite in bedding. Circadian variation in asthmatic shift workers was intimately related to sleep and virtually independent of solar time. Treatment tends to lose its effect as it is discontinued during sleep and this increases the apparent diurnal variation in many patients. Excessive circadian variation may be an important factor in sudden asthma deaths. The importance of effective nocturnal medication is stressed.

Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate.

A computer technique (cosinor analysis) has been used to evaluate circadian rhythms in airway calibre in normals and asthmatics. Two hundred and twenty-one normal subjects recorded peak expiratory flow rate (PEFR) at home four times a day for seven days. Rhythm detection was statistically significant in 145 of them (65.6%) who showed a mean amplitude of 8.3% of individual mean PEFR (+/- SD 5.2%). Amplitude was independent of age, sex, atopy, family history of asthma, and smoking habit. Fifteen of them were also studied three times a day for five days in the laboratory with flow-volume loops. Eleven showed significant PEFR rhythms at home. No single measurement from the flow-volume loop showed periodicity in as many of them but rhythms were now also detected in the other four normal subjects in some components of the loop. Fifty-six asthma patients were studied with a similar protocol of PEFR measurement and compared with the 145 rhythmic normal subjects. Mean phases of the normal and asthmatic rhythms were not significantly different with acrophases (peak of rhythm cycle) at 1557 and 1526 respectively. The mean asthmatic amplitude was, however, significantly greater at 50.9%. Nocturnal asthma, therefore, probably represents an exaggeration of a normal circadian rhythm in airway calibre. The amplitude of the PEFR rhythm is an index of bronchial lability and is thus valuable in monitoring asthma patients. An amplitude of greater than 20% should be a useful screening test for asthma.

Does sleep cause nocturnal asthma?

The effects of sleep interruption and deprivation were studied in 21 patients with nocturnal asthma. Seven patients were awakened at 0200 on three consecutive night and exercised for 15 minutes. This produced no significant improvement in the overnight fall in peak expiratory flow rate (PEFR) compared with a control night of uninterrupted sleep. In a second study in five patients PEFR was measured at two-hourly intervals to estimate the time of onset of the nocturnal fall in PEFR. On three subsequent nights they were awakened and exercised one hour before this time. This also failed to prevent a fall in PEFR by 0600. Eleven patients, who had followed a similar protocol to the second study, were kept awake until after 0300 or later, and PEFR was observed hourly. Six of them (group A) sustained their usual fall in PEFR while awake, proving that sleep was not responsible for their nocturnal asthma. Five patients (group B) showed little fall in PEFR until they were allowed to sleep, when an appreciable fall was noted on waking at 0600. When sleep deprivation was repeated in two patients in group B, however, they sustained falls in PEFR while still awake. We conclude that the circadian rhythm in PEFR is often in phase with the timing of sleep but sleep does not cause nocturnal asthma. Disruption of sleep therefore has no apparent value in the treatment of nocturnal asthma.

Endoscopic palliation of tracheobronchial malignancies.

The prognosis for tracheobronchial tumours remains poor. Most patients can be offered only palliation. When the main symptom is breathlessness or refractory haemoptysis from a large airway tumour endoscopic treatment may be very effective. Over the last decade most attention has focused on the neodymium YAG laser. This often produces dramatic effects but has some important limitations. In the last few years better techniques for stenting and intrabronchial radiotherapy (brachytherapy) have also been developed. This article discusses the range of techniques now available and aims to help clinicians decide which patients may benefit from referral to centres providing these techniques.

Do sympathomimetic amines prevent exercise-induced asthma by bronchodilatation alone?

Seventeen patients with exercise-induced asthma were studied. Eleven patients (cases 7-17), of whom seven were atopic subjects, were given isoetharine or isoprenaline and were subsequently tested for exercise-induced asthma after bronchodilatation had ceased. In two atopic and one non-atopic patients protection was observed which could not be attributed to chance. Two of these three patients were studied again and this phenomenon was repeatable. Prevention of exercise-induced asthma 30 min after inhalation of isoetherine and sodium cromoglycate was compared in 10 patients (cases 1-10), of whom six were atopic subjects. There was no significant difference in the results and protection from isoetharine was not related to the magnitude of its bronchodilator effect. These results suggest that beta-adrenergic agonists may have both bronchodilator and other actions in exercise-iduced asthma. Whether these other actions are anti-alergic is unknown.

Physiological patterns in early morning asthma.

Sixteen asthmatic patients who regularly showed early morning falls in peak expiratory flow rate of more than 25% were studied at 06.00 hours and 14.00 hours. At 06.00 hours considerable deterioration in static lung volumes and airways resistance occurred which was typical of an attack of acute asthma. Blood gas analysis showed less variation, with mild hypoxia and a wide alveolar-arterial oxygen tension gradient throughout the study. Diurnal variation was also seen in the response of maximal mid expiratory flow rates to the inhalation of helium/oxygen mixture in seven patients, but another seven were consistently non-responders. The overall pattern of results suggests that the calibre of both large and small airways decreased at night but improvement was more complete in large airways during the day. Despite these findings patients had few symptoms at 06.00 hours when most of them showed marked reversibility after inhaling aerosol salbutamol. This phenomenon might account for the sudden nature of some asthma deaths as these often occur in the early morning. If this is the case, the minority of patients whose early morning decline in lung function was not immediately reversible would appear to be at greatest risk.

Can patients keep their own peak-flow records reliably?

Fifty patients recorded their peak expiratory-flow rate (P.E.F.R.) in hospital, unaided by nursing staff, five times a day for 5 days. Each patient's readings were randomly and independently checked on two occasions during this period. 69% of checked readings were accurate. Most patients kept satisfactory records as a table, but were less efficient in recording their results on a P.E.F.R. chart. Recording of P.E.F.R. by patients with respiratory disease saves nursing time and provides valuable clinical information.

Asthma: analysis of sudden deaths and ventilatory arrests in hospital.

The incidence of episodes of unexpected ventilatory arrest, some of which led to sudden death, was studied in 1169 consecutive hospital admissions for asthma. Of the most acute cases, 458 were initially managed in a special care unit where only one ventilatory arrest occurred. A further nine cases of arrest, three of which proved fatal, happened on general wards. Accepted clinical criteria of a severe attack were not present in those episodes occurring outside the unit, which were apparently mild attacks. The risk of sudden death could not be related to the severity of the attack but it did correlate with the presence of excessive diurnal variation in peak expiratory flow rate (PEFR). Special treatment of patients with this sign might reduce mortality.

Regular versus symptomatic aerosol bronchodilator treatment of asthma.

Regular treatment with salbutamol or placebo aerosols was compared in a double-blind study in 18 asthma patients. Although symptom scores and respiratory function tests were not significantly different, wheezing attacks requiring additional puffs of a standard salbutamol aerosol were significantly more frequent during the period on placebo when patients were receiving symptomatic treatment only. Thus regular treatment with bronchodilator aerosols provides better control of asthma than symptomatic use alone.