Elective versus symptomatic antibiotic treatment in cystic fibrosis patients with chronic Pseudomonas infection of the lungs.

BACKGROUND: A previous retrospective study suggested that a policy of regular anti-pseudomonal antibiotic treatment improved pulmonary function and increased survival in patients with cystic fibrosis chronically infected with Pseudomonas species. The results of a prospective multicentre study to compare the effects on pulmonary function and mortality of three monthly elective anti-pseudomonal antibiotic treatment with conventional symptomatic treatment are reported. METHODS: Sixty patients with cystic fibrosis, chronically infected with P aeruginosa, were randomised to the two treatment arms (elective or symptomatic) and followed clinically at yearly reviews. The major end points were changes in forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). Survival was a secondary end point. RESULTS: Patients in the symptomatic group received a mean of three antibiotic treatments each year and those in the elective group received four antibiotic treatments during each year of the study. No significant differences in FEV(1) and FVC were found between the two groups after three years. There was a statistically non-significant higher rate of deaths in the elective group (n = 4), three of which were associated with B cepacia infection, compared with the symptomatic group (n = 0). CONCLUSIONS: This study did not demonstrate an advantage of a policy of elective antibiotic treatment over symptomatic treatment in patients with cystic fibrosis chronically infected with Pseudomonas species.

Sputum endothelin-1 is increased in cystic fibrosis and chronic obstructive pulmonary disease.

Many patients with cystic fibrosis (CF) have airflow obstruction, with peribronchial and peribronchiolar fibrosis. Endothelin (ET)-1 is a potent bronchoconstrictor with mitogenic activity for airway smooth muscle. Do the levels of ET-1 in sputum support the putative role of ET-1 in contributing to airway remodelling with airflow obstruction in CF? The levels of ET-1 in plasma, saliva and sputum from 12 adult patients with CF not in exacerbation (spontaneous sputum), 17 normal control subjects (induced sputum) and as an additional control population, nine patients with stable chronic obstructive pulmonary disease (COPD) (seven spontaneous sputum) were measured. Total and differential sputum cell counts were performed. Median (interquartile range) sputum ET-1 level was elevated in CF (77.6 (29.0-122.8) pg x mL(-1)) compared to normal subjects (6.00 (2.8-14.8) pg x mL(-1)) and COPD (16.4 (6.8-38.2) pg x mL(-1)), and in COPD compared to normal subjects. There was a slight elevation of plasma ET-1 level in CF (5.3 (3.2-6.0) pg x mL(-1)) compared to normal subjects (3.1 (1.7-4.4) pg x mL(-1)) and COPD (3.3 (2.7-4.2) pg x mL(-1)). Sputum and saliva ET-1 levels were significantly higher than plasma levels in all groups, suggesting local production or release in the respiratory tract. Sputum differential cell counts revealed pronounced neutrophilia in CF and COPD compared to normal subjects. Sputum endothelin-1 concentrations are elevated in cystic fibrosis sputum compared to chronic obstructive pulmonary disease, and in cystic fibrosis and chronic obstructive pulmonary disease compared to normal subjects. The role of endothelin-1 in contributing to airflow obstruction through bronchoconstriction and mitogenesis in cystic fibrosis needs now to be explored.

Role of heat shock proteins in the pathogenesis of cystic fibrosis arthritis.

BACKGROUND: Arthritis is a well recognised complication of cystic fibrosis. The cause of this arthritis is not yet clear but it is likely to be an immunological reaction to one of the many bacterial antigens to which the lungs are exposed. One such group, the heat shock proteins, (hsp), was investigated. These are immunodominant antigens of a wide variety of infectious microorganisms and have varying amino acid chain sequences, some of which are similar to those found in human tissues. METHODS: Antibodies to human hsp 27 and hsp 90 in the serum of patients with cystic fibrosis, with and without arthritis, and in normal age and sex matched healthy controls were measured. The severity of the cystic fibrosis was assessed by lung function tests and chest radiographs. The nature of the organisms colonising the lungs was determined by bacteriological examination of sputum. RESULTS: Higher mean titres of serum IgG anti-human hsp 27 and hsp 90 antibodies were found in 50 patients with cystic fibrosis than in healthy controls (hsp 27, 0.25 (95% CI 0.19 to 0.33) versus 0.05 (95% CI 0.04 to 0.07); hsp 90, 0.27 (95% CI 0.22 to 0.32) versus 0.11 (95% CI 0.08 to 0.14)). These antibodies were higher in patients in whom the lungs were colonised with Pseudomonas aeruginosa than in those without infection (hsp 27, 0.41 (95% CI 0.17 to 0.63) versus 0.18 (95% CI 0.10 to 0.27); hsp 90, 0.37 (95% CI 0.18 to 0.57) versus 0.22 (95% CI 0.16 to 0.29)). The eight patients with cystic fibrosis with arthritis had higher anti-hsp 27 antibodies (0.48 (95% CI 0.13 to 0.92)) than the 42 patients without arthritis (0.22 (95% CI 0.17 to 0.30)). CONCLUSIONS: These findings suggest that the arthritis associated with cystic fibrosis, despite being seronegative for rheumatoid factor, was associated with more severe lung disease and with a greater inflammatory response to heat shock proteins.

Legionnaires' disease due to Legionella anisa.

The first case of Legionnaires' disease due to Legionella anisa is described. The patient, a 31-year-old man, made a rapid and complete recovery when treated with erythromycin.

Meningioma in a chronic schizophrenic.

A patient with a 27 year history of schizophrenia is described. Post-mortem revealed the presence of a right sided parietal meningioma. It is possible that this lesion caused the schizophrenic symptoms and that earlier investigation might have led to removal of the lesion.

Short duration combination chemotherapy in the treatment of small cell lung cancer.

Ninety five patients (57 with limited disease and 38 with extensive disease) with previously untreated small cell lung cancer were entered into a study of short duration combination chemotherapy with intravenous cyclophosphamide (750 mg/m2) on day 1, adriamycin (40 mg/m2) on day 1, and etoposide VP-16 (100 mg/m2) on days 1, 2, and 3, with the addition on day 10 of methotrexate 50 mg/m2 with folinic acid rescue and vincristine 2 mg. The treatment was repeated on day 22 and only three courses were given. No maintenance chemotherapy was given, though patients with a complete response received radiotherapy (30-40 Gy (3000-4000 rads] to the primary site in most cases. Forty nine patients (86%) with limited disease achieved a response, with 26 (46%) complete remissions. Twenty five patients (66%) with extensive disease had a response, but only eight (21%) had a complete response. Actuarial survival analysis for the whole patient population showed a median survival of 13 months for patients with limited disease and seven months for those with extensive disease. The median survival was 14 months for those patients with limited disease who achieved a complete response, but only 10 months for non-responders. Myelosuppression was the major expression of toxicity. There were three deaths related to treatment and seven patients had febrile episodes during neutropenia that required antibiotics. Mucositis, which was usually mild, occurred in 49% of patients. The primary site was the main site of initial relapse in 56% of the patients who relapsed. Among patients with limited disease who achieved a complete response, relapses at the primary site were less common in those who received radiotherapy (five out of 12) than in those who did not (all eight). The results indicate that this short duration chemotherapy in small cell lung cancer gives response rates and the potential for long term survival similar to those obtained in other series while allowing patients the maximum time free from treatment.

Bowel adenocarcinoma in a patient with cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive condition affecting one in 2,000 live births in the UK. There are few reports of malignant tumours in this condition probably because, until recently, the majority died before the age of 30 years as a result of recurrent and chronic bronchopulmonary infection with impaired growth and development and resistance to infection due to pancreatic malabsorption. We describe an adult male with CF who died from an adenocarcinoma affecting the ileocaecal region of the bowel.

Cystic fibrosis--a review of 26 adolescent and adult patients.

Twenty-six patients, mean age 20.5 years (range 11-33 years) at last assessment or death, attended an adult cystic fibrosis clinic between 1975 and 1983. Twenty-one presented in infancy, and 5 later (3-17 years). Most morbidity was due to recurrent respiratory infection and 5 of the 7 deaths were from respiratory failure. Cor pulmonale occurred in 4 patients, pneumothorax in 3 and severe haemoptysis necessitating lobectomy in 2. Declining spirometric values and persistent isolation of Pseudomonas aeruginosa from sputum samples were associated with a poor prognosis. Minor gastrointestinal symptoms were common (19 patients). Four patients developed intestinal obstruction. Six patients had abnormal liver function tests and one patient died from hepatic cirrhosis. Diabetes was diagnosed in 3 patients and 9 patients experienced joint pains. The prognosis and quality of life for patients with cystic fibrosis appear to be improving, and all but 2 of the patients attending the clinic are at school, university or are employed.

Bronchioloalveolar cell carcinoma: a 21-year retrospective study of cases at the Western Infirmary, Glasgow.

A 21-year retrospective autopsy study of bronchioloalveolar cell carcinoma in the Western District of Glasgow is presented which includes a detailed review of the case notes and post-mortem pathology of 18 patients. Aspects of the histogenesis of the tumour and its prognosis are included in the discussion. It is concluded that bronchioloalveolar cell carcinoma is a valid term which describes a disease entity that is amenable to successful surgical resection when at a limited stage but that in pathological terms it represents a heterogeneous population of tumours.

Vindesine and cisplatin combination chemotherapy compared with vindesine as a single agent in the management of non-small cell lung cancer: a randomized study.

One hundred and five patients with inoperable non-small cell lung cancer were included in a randomized trial comparing the activity of vindesine as a single agent with the combination of vindesine and cisplatin. All patients were previously untreated and the majority (70%) had squamous carcinoma. The overall partial response rates in 88 evaluable patients were 7% for vindesine alone and 33% for the combined regime. There were no complete responders in either arm. The median survival of patients treated with vindesine and cisplatin was 11 months, compared with 4 months in those treated with vindesine alone (P = 0.008). Patients showing a partial or complete response to vindesine and cisplatin survived a median duration of 13 months, compared with 7 months for non-responders (P = 0.03). This survival benefit associated with the combination was particularly apparent for patients with ECOG performance status 0 or 1 (median survival greater than 18 months and 13 months respectively), locoregional disease (median survival 14 months) and squamous cell histology (median survival 13 months). Myelo-suppression was greater with the combination but was not a major treatment problem. Neurotoxicity, which was frequently dose-limiting, was of similar severity in both treatment groups. The results indicate that the combination of vindesine and cisplatin is superior to vindesine alone for remission induction in non-small cell lung cancer and confers a significant survival advantage compared with vindesine alone in patients with favourable prognostic factors.

Theophylline compounds in patients with reversible airways obstruction.

In a double blind cross-over comparison of a single dose 450-mg slow-release aminophylline (SRA) with placebo in eleven patients with stable, reversible airways obstruction SRA produced significantly greater increase in FEV1 and vital capacity from 2 to 9 hr after administration. A second double-blind cross-over comparison of 450-mg SRA with 400 mg of choline theophyllinate (CT) in eleven similar patients showed that SRA produced a slower rise in FEV1 and VC than CT. However, the increase in spirometric readings following SRA was sustained at 9 hr after administration where the spirometric recordings after CT were falling. Whereas CT produced a peak value in plasma theophylline at 1 hr, the highest values after SRA occurred at 4 or 8 hr after administration. The plasma theophylline level at 8 hr after SRA was significantly higher than that following CT. In this single-dose study, plasma theophylline levels obtained were within the normal therapeutic range and this was not exceeded and no side effects were recorded.

A double-blind controlled study comparing temazepam with papaveretum as premedication for fibreoptic bronchoscopy.

One hundred patients undergoing routine fibreoptic bronchoscopy were randomly allocated to receive premedication with either intramuscular papaveretum or oral temazepam in a double-blind manner. They all received atropine before and oxygen during the procedure. Patients found the drugs equally acceptable in terms of discomfort, anxiety and the possibility of repeat bronchoscopy, but more had recall of the procedure with papaveretum. There was no difference in secretions, coughing, relaxation and consciousness, as assessed by the bronchoscopist, but patients who had received papaveretum were more cooperative. Arterial blood gases were performed before and 45 minutes after bronchoscopy. Those given papaveretum had a significant fall in mean arterial oxygen tension of 0.96 kPa, while there was no significant change in the temazepam group. There was also a small mean rise in arterial carbon dioxide tension in both groups, with the mean rise in the papaveretum group (0.625 kPa) being significantly higher than the temazepam group (0.2 kPa). Premedication with temazepam is a useful alternative to papaveretum and has the advantage of oral administration and causing less respiratory depression.

Autologous x-irradiated tumour cells and percutaneous BCG in operable lung cancer.

To determine the value of specific immunotherapy with adjuvant BCG in operable lung cancer, the immunological and clinical results of serial postoperative injections of autologous irradiated tumour cells and BCG were compared with those of a single preoperative injection of BCG in two randomly selected groups of patients undergoing resection of their tumours. There was a significant rise in tuberculin skin reactivity from seven weeks to 11 months after operation in the treated group. Actuarial curves for survival and freedom from tumour recurrence and median survival times showed an advantage for the treated patients who had stage I tumours, but these differences were significant only at the levels p = 0.07 - 0.09. Survival and duration of freedom from tumour recurrence was greater in autograft-treated patients whose skin responded to a weak test dose of dinitrochlorobenzene (DNCB) after sensitisation with 2% DNCB than in control DNCB-positive patients (p = 0.02). There were no significant differences in the actual proportion of patients from each group surviving at two years. The results show that this form of specific immunotherapy with adjuvant may have a beneficial effect in patients with stage I tumours and those who become sensitised to 2% DNCB after the first exposure.

Circulating ACTH and related peptides in lung cancer.

The prevalence of high levels of circulating ACTH-like immunoactivity was determined in 134 patients with lung cancer, using reference ranges from 52 age- and sex-matched patients with non-malignant lung disease. Two studies used ACTH radioimmunoassays with different specificities. Study A used an unextracted plasma or serum assay for total ACTH immunoactivity. High serum ACTH levels occurred in 24% of patients with small-cell carcinoma and 3% of patients with non-small-cell cancer. In patients with small-cell carcinoma, levels were high in 12% with limited disease and 32% with extensive disease. Study B used an ACTH assay after plasma extraction by porous glass, which measured mainly regular 1-39 ACTH. Here no lung-cancer patient had levels above the reference range, suggesting that the high levels in Study A may be due to plasma ACTH components which are poorly extracted by porous glass. It is concluded that high circulating ACTH immunoactivity occurs in a minority of patients with lung cancer, particularly those with extensive small-cell carcinoma. Indirect evidence suggests that the high ACTH levels detected with assays for total ACTH are due to molecular forms other than 1-39 ACTH, probably high-mol.-wt species.

Diffuse malignant pleural mesothelioma in Glasgow.

Thirty-two patients seen in one area between 1974 and 1980 with a diagnosis of malignant pleural mesothelioma are reviewed retrospectively. Asbestos contact, often in the shipyards, was found in 80%. The average age at diagnosis was 64 years and chest pain or breathlessness were the most common initial symptoms. Radiology usually confirmed a pleural effusion, but rarely also showed pleural plaques or asbestosis. The most useful diagnostic investigation was pleural biopsy, with a 59% success rate. Post mortem examinations showed widespread infiltration of adjacent tissues in many, with haematogenous metastases in 52%. Prognosis was poor, with an average survival of 40 weeks from presentation. No treatment improved life expectancy. Thoracotomy was followed by painful chest wall masses. The incidence of mesothelioma in our area is six times higher than in the rest of Scotland. As the disease has a long latent period between asbestos exposure and appearance, it will be many years before this rate is significantly reduced.

Fatal disseminated BCG infection in an 18-year-old boy.

Death from disseminated infection with BCG (bacille Calmette-Guérin) after routine vaccination is rare, and various immune defects may be responsible. An 18-year-old boy died with widespread lymph-node, bone, lung, and liver involvement 6 years after BCG vaccination. Total numbers of B lymphocytes and T lymphocytes were normal, but T lymphocytes, while transforming normally in the presence of non-specific mitogens, did not transform in the presence of purified protein derivative. Delayed-type hypersensitivity skin tests were negative. Monocytes containing alpha-naphthylacetate esterase were absent.

Cystic fibrosis in adolescents and young adults.

With the early diagnosis of cystic fibrosis and the better management of these patients in childhood increasing numbers are surviving to adult life. The main problem requiring continuous medical care in the older cystic fibrosis patient is persisting and often progressive chest disease. For this reason the cystic fibrosis clinic for adolescents and young adults was started in the Western Infirmary in 1975. This paper presents our observations on 13 patients who had attended between 1975 and 1977. Eleven patients are alive and well and have shown no evidence of deterioration over this period. Ten are at school or in regular employment. With optimum medical supervision it is possible to give young adults with cystic fibrosis a worthwhile existence.

Cell-mediated immunity in operable bronchial carcinoma: the effect of injecting irradiated autologous tumour cells and BCG.

In 52 patients undergoing tests of cell-mediated immunity before surgical resection of bronchial carcinoma a positive tuberculin test result was found in 71% compared with 68% of age- and sex-matched controls. Sensitisation to DNCB occurred in 52% of 37 patients but in 78% of controls. There was depression of lymphocyte transformation by PPD in 19 patients compared with controls (P=0.001), but there was no difference in lymphocyte transformation by PHA or pokeweed mitogen between 34 patients and controls. In a pilot study patients were randomly allocated to autograft (eight) or non-autograft (seven) groups. The autograft group were given an intradermal injection of a suspension of irradiated autologous tumour-cells mixed with intradermal BCG on the day of operation. Tests of cell-mediated immunity were repeated two weeks after operation. Five patients in each group received a course of radiotherapy to the mediastinum three weeks after operation. There was a rise in cutaneous tuberculin reactivity (P=0.08) and total leucocyte count (P=0.09) in the autograft group postoperatively with a fall in total lymphocyte and T lymphocyte counts in the non-autograft group (P less 0.05). These differences, however, were not followed by any difference in the frequency of tumour recurrence or the survival rate two years after operation. The results show that the immunological surveillance mechanism is impaired even in patients with early bronchial carcinoma and that it is possible to overcome postoperative immunological depression with specific immunotherapy combined with BCG. This treatment did not produce any clinical advantage in this small number of patients and the skin lesions caused the patients considerable discomfort.

Serum biochemical markers in lung cancer.

The prevalence of elevated serum levels of 5 potential tumour-associated antigens was determined in patients with lung cancer sampled at the time of initial presentation, using age- and sex-matched patients with benign lung disease as controls. Elevated levels (greater than upper 95th centile of controls) were found as follows: carcinoembryonic antigen (CEA), 17%; pregnancy-associated alpha-macroglobulin (PAM), 16%; casein 14%; human chorionic gonadotrophin (HCG) 6%; alpha-foetoprotein (AFP), 1.5%. The prevalence of elevated CEA levels (but not other markers) was higher in patients with evidence of extra-thoracic tumour spread (23%) mainly due to anaplastic tumours and adenocarcinomas. A degree of concordance of elevated marker levels occurred with CEA, HCG, casein and AFP, but there was a striking discordance of elevated CEA and PAM levels. Simultaneous assays of CEA and PAM will detect the majority of patients with elevations of any of the markers studied, and are likely to be the most useful biochemical markers in following the response of lung tumours to therapy.