Summary of the British Thoracic Society guidelines for advanced diagnostic and therapeutic flexible bronchoscopy in adults.

This new guideline covers the rapidly advancing field of interventional bronchoscopy using flexible bronchoscopy. It includes the use of more complex diagnostic procedures such as endobronchial ultrasound, interventions for the relief of central airway obstruction due to malignancy and the recent development of endobronchial therapies for chronic obstructive pulmonary disease and asthma. The guideline aims to help all those who undertake flexible bronchoscopy to understand more about this important area. It also aims to inform respiratory physicians and other specialists dealing with lung cancer of the procedures possible in the management and palliation of central airway obstruction. The guideline covers transbronchial needle aspiration and endobronchial ultrasound-guided transbronchial needle aspiration, electrocautery/diathermy, argon plasma coagulation and thermal laser, cryotherapy, cryoextraction, photodynamic therapy, brachytherapy, tracheobronchial stenting, electromagnetic navigation bronchoscopy, endobronchial valves for emphysema and bronchial thermoplasty for asthma.

The development of the first nurse-led bronchoscopy post in the United Kingdom.

Nurses routinely practice Gastrointestinal endoscopy in the United Kingdom (UK) but, to our knowledge, bronchoscopy has never been introduced as a nursing discipline. The need for a nurse bronchoscopist was identified within our respiratory unit and the post was developed. This process involved: (1) seeking a precedent for the role of nurse bronchoscopist, (2) designing an appropriate teaching programme, (3) obtaining hospital accreditation for the programme, (4) supervising and completing the training, and (5) implementing a nurse-led bronchoscopy service. The development phase took approximately 1 year. No precedent was found for nurse-led bronchoscopy in the UK or elsewhere. The training programme defined minimum entry requirements and was modelled on UK nurse GI endoscopy training and the British Thoracic Society bronchoscopy guidelines. The role of nurse bronchoscopist was deemed to comply with professional codes of nursing practice by the chief nurse and the hospital management board authorised a service framework for the post. The first trainee completed the programme in January 2003 and has now examined 125 patients independently [endobronchial tumour biopsy hit-rate = 95% (95% CI 76-99%)]. The post of nurse bronchoscopist has been successfully developed and accredited within our hospital.

Polymorphisms in the NAD(P)H: quinone oxidoreductase gene and small cell lung cancer risk in a UK population.

NAD(P)H: quinone oxidoreductase (NQO1) protects the cell against cytotoxicity by reducing the concentration of free quinone available for single electron reduction. The NQO1 gene is polymorphic and the variant protein exhibits just 2% of the enzymatic activity of the wildtype protein. In this study, we investigated NQO1 genotype in relation to lung cancer risk in patients attending a Manchester bronchoscopy clinic. The cases were patients with a current, or history of, malignant tumour of the lung, trachea or bronchus. The control group were all other patients attending the clinic who had never been diagnosed with a tumour. DNA extraction from bronchial lavage or blood samples and genotyping was successfully carried out for 82 of the cases and 145 controls. Patients carrying at least one variant allele were found to have almost a 4-fold increased risk of developing small cell lung cancer (adjusted OR=3.80, 95% C.I. 1.19-12.1). No association between NQO1 genotypes and non-small cell lung cancer risk was found. Furthermore, the excess small cell lung cancer risk associated with non-wildtype NQO1 genotypes was only apparent in heavy smokers where there was a >10-fold increased risk (adjusted OR=12.5, 95% C.I. 2.1-75.5). These results suggest that the NQO1 protein may be involved in the detoxification of those carcinogens associated with the development of small cell lung cancer. Individuals with reduced enzyme activity, due to a polymorphism in this gene, may therefore have an increased risk of developing this disease.

Treatment of endobronchial metastases with intraluminal radiotherapy.

Metastasis to the lung occurs quite commonly from certain types of extrapulmonary primary carcinoma. Spread to the bronchial lumen is relatively rare. When this does occur, symptoms resembling those of primary bronchial carcinoma are often present, in association with partial or complete obstruction of the bronchial lumen. Palliation of such symptoms is possible with the use of intraluminal radiotherapy (ILT). Between 1990 and 1998, 37 patients with endobronchial metastases were treated using this modality; a single fraction of radiation was delivered by the remote afterloading high dose rate microSelectron system. Data regarding these patients' characteristics and outcome are presented, following a retrospective review of case notes. The commonest symptoms were dyspnoea, cough and haemoptysis; the commonest primary tumour sites were breast, colorectum, oesophagus and kidney. Twenty-four (64.9%) patients had some improvement in symptoms following treatment. Mean overall survival was 280 days, range 9-1145 days. No serious adverse effects occurred. ILT is a relatively simple, safe and effective treatment in the palliation of symptoms due to endobronchial metastases.

Gonadotrophin-releasing hormone analogues: a novel treatment for premenstrual asthma.

Premenstrual exacerbation of asthma, as reflected by a reduction in peak expiratory flow rate (PEFR), has been demonstrated in 40-100% of female asthmatics. Epidemiological data demonstrate that admission to hospital with an exacerbation of asthma occurs more frequently perimenstrually. Therapeutic interventions aimed at modifying this precipitating factor, however, remain limited. We report on a 32-yr old female with asthma in whom a marked increase in symptoms and reduction in PEFR occurred premenstrually, necessitating recurrent admissions to hospital. Frequent severe exacerbations resulted in the chronic use of oral maintenance corticosteroids. In order to suppress gonadotrophin secretion and ovarian function, a long-acting gonadotrophin-releasing hormone analogue was administered with a view to inducing a reversible menopause. This resulted in improvement in respiratory symptoms, the absence of PEFR dips premenstrually, a reduction in maintenance prednisolone dosage and no further hospital admissions during a follow-up period of 14 months. The authors propose that gonadotrophin-releasing hormone-analogue therapy is a rational and innovative adjuvant treatment worthy of further study in cases of severe premenstrual asthma.

Association between O6-alkylguanine-DNA-alkyltransferase activity in peripheral blood lymphocytes and bronchial epithelial cells.

The activity of the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase (ATase) may be a risk factor in the pathogenesis of lung cancer. ATase activity has previously been measured in peripheral blood lymphocytes (PBLs), cell extracts from bronchoalveolar lavage fluid, and cell homogenates from resected lung tissue. However, it is not clear whether ATase activity in these samples correlates well with the activity found in bronchial epithelial cells, the progenitor cells for the main types of lung cancer. In this study, cell extracts were prepared from PBLs, bronchial lavage (BL) fluid, and bronchial brushings from normal lung in 20 patients attending for routine bronchoscopy. Bronchial brushing sampled a significantly greater proportion of bronchial epithelial cells than did BL [88+/-9% (mean+/-SD) versus 39+/-19%; P < 0.0001]. ATase activity was determined in each of the cell extracts and was found to be higher in PBLs than in bronchial brushings (P = 0.005) and higher in bronchial brushings than in BL (P = 0.005). No correlation in ATase levels was observed between any of the three samples. We conclude that bronchial brushing is a more specific and reliable way of sampling bronchial epithelial cells than BL and that it samples enough cells for ATase activity to be determined. In addition, in terms of the activity of this potentially critical DNA repair enzyme, PBLs, and cell extracts obtained from BL may not provide good surrogate tissue for bronchial epithelial cells, the critical targets for carcinogenesis.

Massive haemoptysis death and other morbidity associated with high dose rate intraluminal radiotherapy for carcinoma of the bronchus.

Four hundred and six patients with primary non-small cell carcinoma of the bronchus causing symptoms due to endobronchial disease, were treated with intraluminal radiotherapy (ILT) using the microSelectron-HDR machine at the Christie Hospital, Manchester, between April 1988 and the end of 1992. An assessment of morbidity for this treatment is presented, particularly with regard to the risk factors and causes of massive haemoptysis death. The most common early side-effect was a mild transient exacerbation of cough which usually resolved within 2-3 weeks. At various times following ILT treatment 83 bronchoscopies were carried out randomly in 55 patients. In bronchoscopies carried out within the first 3 months following ILT, no tumour was visible in 80% of cases. A mucosal radiation reaction score (RRS) was used to grade bronchoscopic appearance after ILT treatment. Overall, 55% of bronchoscopic examinations showed some degree of mucosal radiation reaction. The majority of radiation reactions from 6 months onwards after ILT demonstrated a degree of fibrosis. A radiation reaction was seen more frequently after treatment with 2000 cGy as opposed to 1500 cGy at 1 cm from the central axis of the radiation source. Thirty-two patients were identified who had died from massive haemoptysis (MH) as a terminal event. A Cox multivariate regression analysis showed that the treatment-related factors of increased dose at first ILT (P = 0.004), prior laser treatment at the site of ILT (P = 0.020) and second ILT treatment in the same location as the first ILT treatment (P = 0.047), all significantly increased the relative risk of MH death compared with their effect on the relative risk of death from other causes (OC). (In addition a fourth treatment-related factor, namely the concurrent use of ILT and external beam radiotherapy (EB) had a P value of 0.08). Twenty out of 25 assessable MH-death patients (80%) had evidence of recurrent or residual tumour before death but 5 patients (20%) did not. For surviving patients the instantancious risk of death at any one time (the cause-specific death rate expressed as deaths per 100 cases per month), showed a sharp peak for MH deaths between 9 and 12 months post ILT in contradistinction to OC death where the peak was between 3 and 6 months post ILT. These findings may imply a role for late radiation reaction in the treatment-related risk factors identified as increasing the relative risk of MH death and possible mechanisms are discussed. The results have implications for treatment regimes that use a dose of 2000 cGy at 1 cm in a single fraction technique, that have a high frequency of previous laser treatment, that use multiple, repeated ILT treatments in the same location and that use ILT concurrently with EB.

Long-term survival and symptom palliation in small primary bronchial carcinomas following treatment with intraluminal radiotherapy alone.

Between April 1988 and December 1992, 37 patients with small, previously unirradiated, primary non-small cell carcinomas of the bronchus causing symptoms due to endobronchial disease were treated at the Christie Hospital, Manchester, with a single fraction of high dose rate intraluminal radiotherapy (ILT) using the microSelectron-HDR machine. Small primary (SP) lesions were defined as being less than 2 cm in diameter in a direction perpendicular to the central axis of the iridium-192 treatment source. Fifteen patients (41%) were treated to a dose of 15 Gy and 22 patients (59%) to 20 Gy at a distance of 1 cm from the central axis of the source. At 6 weeks following ILT, improvement in symptoms was seen in the following percentages of patients: haemoptysis 96%, pulmonary collapse 69%, cough 55% and dyspnoea 52%. The magnitude of improvement in these symptoms was largely maintained in patients surviving to 4 months and then 12 months post-ILT. Median actuarial survival was 709 days, 2-year survival 49.4% and 5-year survival 14.1%. Overall, there was no significant difference in survival after treatment with 20 Gy compared with 15 Gy at 1 cm. At the close of study, there were four patients still alive without disease recurrence with survivals of 38, 48, 49 and 63 months. All had had biopsy-proven squamous cell carcinomas and all had been treated with 20 Gy at 1 cm. Five patients died from massive haemoptysis as a terminal event at 4, 9, 9, 10 and 11 months post-ILT, well below the median survival for this group of patients. Again, all had been treated with 20 Gy as opposed to 15 Gy at 1 cm. Over the same time period, 287 patients with non-small cell carcinomas of more than 2 cm in diameter (large primary lesions, LP), were treated with a single fraction of ILT only, as their initial treatment. A consistently greater percentage of patients with SP lesions showed an improvement in the symptoms of haemoptysis and pulmonary collapse when compared with patients with LP lesions. Patients with LP lesions demonstrated a decreased actuarial survival when compared with SP lesions, with median survival being 156 days, 2-year survival 3.1% and no survivors beyond 39 months. This study demonstrates that, in patients with small endobronchial carcinomas a single fraction of ILT can give efficient palliation of symptoms and lead to long term disease-free survival, but that a dose of 20 Gy may be at the limit of bronchial radiation tolerance for a single dose technique employing a high dose rate source.

High dose rate intraluminal radiotherapy for carcinoma of the bronchus: outcome of treatment of 406 patients.

In April 1988 the Christie Hospital started using the microSelectron-HDR machine to deliver intraluminal radiotherapy (ILT) to inoperable bronchial carcinomas causing symptoms due to endobronchial disease. Results of treatment in the first 406 patients with primary non-small-cell carcinoma are presented. Three main categories of patient were defined. Category 1 consisted of 324 patients (79.8%) who were previously unirradiated and received a single fraction of ILT as their primary treatment, mostly to a dose of 1500 cGy (76%) or 2000 cGy (23%) at 1 cm from the centre of the iridium-192 treatment source. The percentage of these patients whose symptoms or signs were improved at 6 weeks following ILT were as follows: stridor 92%, haemoptysis 88%, cough 62%, dyspnoea, 60%, pain, 50% and pulmonary collapse, 46%. Approximately two-thirds of these patients (67.3%) derived long lasting palliation and required no further treatment during their lifetime. The other third of patients needed subsequent treatment at some stage because of recurrence of their symptoms and in this situation external beam radiotherapy (EB) or a repeat ILT treatment was effectively utilised. Category 2 consisted of 65 patients (16%) who had previously received EB but required ILT when their tumour recurred. At 6 weeks post-ILT levels of symptom palliation were broadly similar to those obtained if ILT was used in previously unirradiated individuals, although the improvement was not so well sustained with time and only 7% showed improvement in pulmonary collapse at 6 weeks. Category 3 consisted of 17 patients (4.2%) in whom ILT was used concurrently with EB as a combined initial treatment. Similar levels of palliation were seen when compared with patients who received a single ILT treatment only. Overall, ILT was well tolerated in terms of early and late morbidity. In conclusion, the efficiency of a single ILT treatment in palliating symptoms due to endobronchial tumour in previously unirradiated individuals is comparable with that reported in series where treatment for advanced lung cancer combines a prolonged course of EB concurrently with several ILT treatments.

Intraluminal irradiation for the palliation of lung cancer with the high dose rate micro-Selectron.

Fifty patients with inoperable, symptomatic endobronchial carcinoma were treated by a single exposure of intraluminal radiotherapy. A high dose rate afterloading system (the micro-Selectron-HDR) was used to minimise radiation exposure for staff. Haemoptysis was relieved in 24 of 28 patients, breathlessness in 21 of 33 patients, and cough in nine of 18 patients. Radiological collapse resolved in 11 of 24 patients. Treatment was given on an outpatient basis and was well tolerated. Intraluminal radiotherapy appears to offer an effective alternative to conventional fractionated external beam radiotherapy.

A clinicopathological study of the paraneoplastic neuromuscular syndromes associated with lung cancer.

The highest incidence of remote neuromuscular disorders in cancer has previously been reported in lung carcinoma. The clinical incidence of neuromuscular disorder was estimated and correlated with muscle histology and the histological type of lung tumour in 100 patients with lung carcinoma who were studied prospectively. Thirty-five patients had small cell carcinoma and 65 patients non-small cell lung cancer. Clinically, 33 patients had a polymyopathy, of whom 18 had a cachectic myopathy and 15 had a proximal myopathy (two patients had Lambert-Eaton myasthenic syndrome, one presented with dermatomyositis and one had evidence of ectopic ACTH production). Cachexia was more common in non-small cell cancer; proximal myopathy was more common in small cell cancer. Ninety-nine patients had abnormal muscle histology; 74 had type II atrophy, 12 had type I and II atrophy, one had type I atrophy and 12 had necrosis. The majority of patients were affected sub-clinically and the clinical entities of cachectic and proximal myopathy did not correspond to previous pathological classifications. Atrophy was not related to the duration of tumour symptoms, ageing, clinical type of myopathy or histological type of lung tumour, and was statistically different from that seen in controls. Qualitatively, the presence of weight loss, muscle wasting and metastatic disease were not factors in the development of atrophy. Similarly, necrosis was not related to the type of lung tumour, the presence of metastases, ageing, weight loss, muscle wasting, duration of tumour symptoms or the clinical form of myopathy. This study demonstrates that lung carcinoma has a direct effect on the motor unit, including atrophy, a necrobiotic myopathy and Lambert-Eaton myasthenic syndrome. Clinical assessment does not accurately assess the 'remote' neuromuscular effects of cancer on the motor unit.

Atraumatic suppurative mediastinitis and purulent pericarditis due to Eikenella corrodens.

Atraumatic suppurative mediastinitis is an uncommon infection. A case with an associated purulent pericarditis caused by Eikenella corrodens is reported.

Ifosfamide, etoposide, and thoracic irradiation therapy in 163 patients with unresectable small cell lung cancer.

One hundred sixty-three patients with small cell lung cancer were treated with six courses, at 3-week intervals, of ifosfamide (5 g/m2) with mesna and etoposide. Thoracic radiotherapy was delivered to the limited stage (LS) patients. The complete response rate (CR, determined clinically and radiologically) was 76% for the 78 LS patients with a further 14% partial response (PR). The majority of the CRs were confirmed on a follow-up bronchoscopy. The CR rate was 27% for extensive stage (ES) patients with another 38% undergoing a partial response. The median survival for LS patients was 11 months, (16 months for CR confirmed by rebronchoscopy) and 8 months for ES patients. The 2-year actuarial survival for LS patients is 27%, follow-up ranges from 12 months to 30 months with a median of 22 months. Toxicity was not severe for the patient population, of whom only 20% had a good performance status before chemotherapy. Parental antibiotics were required on 4% of all 844 chemotherapy courses and 12% of courses were delayed due to side effects. The majority of responses occurred within the first two courses of chemotherapy and there was a corresponding improvement in the patients' symptoms and performance status. The regimen produced rapid tumor response with corresponding improvement in symptoms without marked toxicity and allowed further treatment development.

Expression of epidermal growth factor receptor (EGF-R) in human lung tumours.

Epidermal growth factor receptor (EGF-R) expression was assessed in 63 lung tumour samples with a monoclonal antibody (EGF-R1) by indirect immunoperoxidase staining on cryostat sections. All 15 small cell lung cancer samples were negative whereas over 80% of the 48 non small lung cancer stained positively. In 30 bronchial biopsies two monoclonal antibodies against the cytoplasmic part of the EGF-R were evaluated. These antibodies showed weaker staining than EGF-R1. No additional or enhanced staining as compared with EGF-R1 was observed, suggesting a lack of enhanced expression of a truncated EGF-R analogous to the v-erb-B oncogene product. Monoclonal antibodies against the EGF-R may be helpful diagnostically in differentiating small cell from non small cell lung cancer and may also be important in elucidating biological differences in primary lung cancer.

Preoperative and postoperative pulmonary function tests in patients with atrial septal defect and their relation to pulmonary artery pressure and pulmonary:systemic flow ratio.

Pulmonary diffusing properties and lung volumes were investigated in 44 patients with atrial septal defect, and in 30 of them preoperative and postoperative data were obtained. The patients were divided into three groups according to mean pulmonary artery pressure: less than or equal to 15 mm Hg (group 1), 16-29 mm Hg (group 2), and greater than or equal to 30 mm Hg (group 3). Patients in groups 1 and 2 had a high carbon monoxide transfer test which became normal after surgical correction of their septal defect. In group 3, the carbon monoxide transfer test was normal both before and after operation. As mean pulmonary artery pressure increased there was a progressive reduction in both forced expiratory volume in one second and vital capacity. Patients in group 3 had a low forced expiratory volume in one second, a low vital capacity, and a reduced forced expiratory volume in one second:vital capacity ratio. These abnormalities were not corrected by surgical closure of the septal defect. Formulas were derived from the lung function data, to predict the mean pulmonary artery pressure and the pulmonary:systemic flow ratio. The values predicted when these two formulas were applied to data obtained for patients in this study correlated well with measured values.

Three months' treatment with cyclophosphamide, VP-16-213 followed by methotrexate and thoracic radiotherapy for small cell lung cancer.

One hundred eleven patients with inoperable but limited-stage small cell lung cancer were treated with three courses of cyclophosphamide (1.5, 2.5, and 3.5 g/m2, respectively) and VP-16-213 followed by methotrexate and thoracic radiotherapy. The total duration of treatment was 3 months. Patients were included who had pleural effusions, contralateral neck nodes, and bone marrow infiltration. The complete response (CR) rate was 56%, the majority confirmed by repeat bronchoscopy, with an 81% overall response rate. The minimum follow-up was 14 months. Median survival for all 111 patients was 11 months and 14 months (1-34+) for complete responders; the median survival was also 11 months for the 91 patients with conventional limited-stage disease, although 15 of the 19 patients alive at 14 months or more were from this subpopulation. There was no significant difference in the survival of those CR patients whose response was confirmed bronchoscopically and patients whose CR was assessed only radiologically and clinically. Forty-four patients with leukopenia (less than 1000 cells/microliter) received intravenous antibiotics for malaise and suspected infection. Close monitoring between treatments and direct access of patients to the hospital was encouraged. The majority of patients improved symptomatically as assessed by Karnofsky and Respiratory scores. These results support the view that short but intensive treatment without long-term or maintenance chemotherapy is beneficial.

Moderate to high dose cyclophosphamide and intercalated Corynebacterium parvum in patients with metastatic lung cancer.

Thirty-nine patients with histologically proven widely metastatic bronchogenic carcinoma were treated with cyclophosphamide and Corynebacterium parvum. The dosage of cyclophosphamide was higher than conventional as previous work had indicated better results with increased dosage. Experimental work had suggested that the addition of Corynebacterium parvum would increase the antitumour effect and possibly reduce the cyclophosphamide induced granulocytopenia. A short treatment programme using three i.v. injections of cyclophosphamide, 1.5 g/m2, 2.5 g/m2 then 3.5 g/m2, at 3 week intervals were given. Four days after each cyclophosphamide injection, C. parvum 2 mg/m2 i.v. was administered. An overall 38% tumour response rate was observed, 18% for patients with non-small-cell carcinoma and 65% for small-cell carcinoma patients. The median survival for the 39 patients was 5 months (range 1-16+ months). These results, particularly for the non-small-cell patient group are comparable to those obtained with intensive combination chemotherapy regimens administered intermittently over much longer periods. An important consideration, objectively assessed in the present study, was the effect of treatment on quality of life and breathlessness. Improvement was noted not only in those patients with tumour response but also in a proportion of those who did not fulfil the criteria of response. Toxicity was also carefully assessed and, although the cyclophosphamide dosages were higher than conventionally used, no undue problems were noted. The addition of C. parvum did not have any noticeable beneficial effect. Cyclophosphamide given at dosages higher than is usual but which do not require bone marrow rescue is worthy of further study.

Hypertrophic osteoarthropathy: two unusual causes.

Two patients with hypertrophic osteoarthropathy of unusual aetiology are described. The first patient developed the condition in association with oesophageal carcinoma and the second as a complication of active pulmonary tuberculosis. In the second case, substantial resorption of new bone was seen following treatment.