Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM. To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in approximately 10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patient's performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.

Eighth international mesothelioma interest group.

The eighth International Mesothelioma Interest Group (IMIG) meeting was held in Chicago, IL, United States, in 19-22 October 2006 to discuss mesothelioma - the cancer often linked to asbestos exposure. It is a very aggressive malignancy with a median survival of less than 1 year from diagnosis. Millions of people have been exposed worldwide to asbestos, especially during the second half of the twentieth century when asbestos use increased significantly. The tons of asbestos utilized in the past remain a health hazard for current and future generations because asbestos is difficult to be disposed off. This makes asbestos and mesothelioma research a public health issue in addition to a medical problem. Moreover, the very high costs of asbestos litigation have a significant impact on the whole economy. In the United States, up until 2001, defendant companies had paid 54 billion dollars in claims and estimated future liabilities ranged from 145 to 210 billion. Therefore, asbestos research is of great interest to a large audience that includes patients, millions of asbestos-exposed individuals, scientists, physicians, public health officials, politicians, unions of asbestos workers, lawyers and the public at large. During the past few years, there has been significant progress in understanding the process of mineral fiber carcinogenesis and mesothelioma pathogenesis. With improved understanding of the pathogenesis of mesothelioma, new diagnostic, preventive and therapeutic options are being developed. A total of 247 papers were presented at the IMIG: the abstracts of these presentations were published in Lung Cancer, Supplement 1, October 2006. Here, experts in different disciplines critically review some of the most exciting presentations of the IMIG meeting. The result is a comprehensive review of the research field of asbestos carcinogenesis and mesothelioma, and of the progress that has been made in recent years in both basic and clinical sciences.

Feasibility of home delivery of pemetrexed in patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: To evaluate the feasibility and adherence to home delivery (HD) of pemetrexed maintenance treatment in patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC). MATERIALS AND METHODS: Exploratory, prospective, single-arm, Phase II study in advanced nsqNSCLC patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 that did not progress after 4 first-line induction cycles of a platinum doublet. The first cycle of pemetrexed (500mg/m(2)) was hospital administered, further cycles were HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or treatment discontinuation due to HD) as primary endpoint, and by health-related quality-of-life (HRQoL: EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, overall survival (OS), and safety. RESULTS: 52 patients (UK & Sweden) received a median of 4 (range 1-19) pemetrexed maintenance cycles. Adherence rate up to Cycle 6 was 98.0% (95% confidence interval [CI]: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (patient decision), and 1 after Cycle 6 (non-compliance with oral dexamethasone). 87% (33/38) of the patients preferred home to hospital treatment and in 90% (28/31) of cases, physicians were satisfied with distant management of patients. During HD Cycles 2-4 mean change from baseline ranged from 3.0 to 7.7 for EQ-5D visual analog scale. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD-related adverse event (device-related infection, Grade 2) and 1 patient died after Cycle 1, before HD, due to a possibly drug-related atypical pneumonia. CONCLUSION: HD of pemetrexed maintenance treatment in patients with advanced nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management.

Pleural plaques and risk for bronchial carcinoma and mesothelioma. A prospective study.

From the general population in the county of Uppsala, Sweden, 1,596 men with pleural plaques fulfilling strict radiologic criteria were identified from 1963 until June 1985. The men have been followed prospectively for 16,369 person-years. The number of mesotheliomas and bronchial carcinomas was compared with the age- and year-specific expected incidence from the official cancer registry of Sweden. Fifty bronchial carcinomas occurred, while 32.1 were expected after correction for smoking habits, a difference which was statistically significant. Patients with radiologic asbestosis were overrepresented among those with bronchial carcinoma. The risk for patients with pleural plaques without asbestosis was increased 1.4 times, which was statistically significant. There were 9 mesotheliomas, while only 0.8 were expected. The mean latency time from first exposure to diagnosis of bronchial cancer was 44.1 years and for mesothelioma was 48.1 years. Thus, pleural plaques on the chest roentgenogram indicate significant exposure to asbestos, with an increased risk for mesothelioma and possibly also for bronchial carcinoma. Any person found to have plaques on chest roentgenogram should be informed of them and should be persuaded to stop smoking.

Rounded atelectasis. Clinical experience with 74 patients.

Rounded atelectasis is an atelectasis of a peripheral part of the lung due to pleural adhesions and fibrosis causing deformation of the lung and bending of some small bronchi. From 1970 to 1986, some 74 patients with rounded atelectasis have been seen at the Lung Department. Sixty-four of these patients had been exposed to asbestos. The lesion was secondary to a benign asbestos pleurisy in nine patients and resulted from a slowly increasing pleural fibrosis in 13 patients; in the remaining 39 patients with exposure to asbestos, rounded atelectasis was a sudden finding, with earlier roentgenograms showing only plaques or being normal. Three patients had bilateral lesions, and one had no fewer than three small rounded atelectases. All of the asbestos-exposed patients were men. Ten patients (four women and six men) had not been exposed to asbestos. Two of these cases occurred after trauma and four after a pleural exudate. One of the latter was the only one which disappeared spontaneously. The lingula was affected in 33 cases, the middle lobe in 16, the right lower lobe in 12, the left lower lobe in 11, the right upper lobe in six, and the left upper lobe (except the lingula) in one. Nine patients underwent surgery. Operation should be avoided; the typical roentgenologic and CT findings combined with negative results of bronchoscopy (and, in some cases, fine-needle biopsy) will suffice to exclude malignancy.

Chyliform (cholesterol) pleural effusion.

Chyliform pleural effusions are a little known occurrence only sparingly reported in the literature. At the lung department in Uppsala, Sweden, 11 cases have been seen the last few years. Typically, the exudate develops in a long-standing pleural thickening resulting from therapeutic pneumothorax many years earlier. The exudate contains a high level of cholesterol, probably breakdown products from blood cells. It is usually sterile, and only very rarely can one find tubercle bacilli growing from it. There is a tendency toward recurrence. If the patient benefits clinically from aspiration of the fluid, decortication is indicated.

Large emphysematous bullae. Successful treatment with thoracoscopic technique using fibrin glue in poor-risk patients.

Five patients with poor lung function (FEV1, 0.8 to 1.0 L; MVV, 27 to 36 L/min) and large emphysematous bullae were operated on. Fibrin glue was introduced into the bullae through a thoracoscope. The results have been excellent and no serious perioperative or postoperative complications have occurred. The patients have all improved clinically and are very satisfied with the results. Postoperatively, FEV1 was between 1.0 and 1.2, and MVV was 30 to 52 L. The clinical improvement was, however, larger than these figures illustrate. Our preliminary experience using this technique suggests that it can be used in patients with very low lung function with a minimal risk. We propose that all patients with severe emphysema should be screened for bullous components because improvement might be possible by operation with this minimally traumatizing technique.

Chlamydia pneumoniae may be associated with lung cancer. Preliminary report on a seroepidemiological study.

Material from 117 consecutive patients with lung cancer was investigated with respect to serological markers for chronic Chlamydia pneumoniae infection. Specific C. pneumoniae IgA antibodies were found significantly more often in patients with lung cancer than in control groups with coronary heart disease and in healthy controls, even after adjustment for smoking. The results suggest that chronic C. pneumoniae infection is common in patients with lung cancer.

Long-term survival of patients with lung cancer from a defined geographical area before and after radiological screening.

In the County of Uppsala, Sweden, a general health survey including a chest roentgenogram was operational from the late 1960s until the end of June, 1985. The screening was offered every 2 years and participation was about 70%. From the local cancer registry all cases of lung cancer during the period 1980-1990 aged 75 or less were obtained and their survival and mode of discovery investigated. Only WHO I-IV and undifferentiated cancers verified histologically were included. Twenty-eight cancers (11.5%) were discovered in the survey and these patients had a very good prognosis compared to those who presented with symptoms. During the health survey there were 35 of 244 (14.3%) who survived more than 4 years, and after the survey this figure was 34 out of 265 (12.8%), a nonsignificant difference. Survival for patients with squamous cell carcinoma or adenocarcinoma discovered in the health survey was much improved, and for these two groups combined the 4-year survival was 41.7% compared to 10.3% for those discovered by symptoms (P < 0.001). Thus, survival of patients with lung cancer of squamous cell or adenocarcinoma types can be improved by screening, but unfortunately, only few of the cancers will be discovered in this way, so the total impact of screening will be small.

Prognostic value of malignant cells in pleural lavage at thoracotomy for bronchial carcinoma.

Despite seemingly radical surgery many patients operated on for bronchial carcinoma will die from their disease. Some patients might benefit from postoperative treatment and a prognostic factor that could identify those with an increased risk for tumor relapse would be of great clinical importance. One possible such factor is the occurrence of malignant cells in pleural lavage performed at operation. To test this hypothesis 224 consecutive patients who had been operated on due to verified or strongly suspected bronchial carcinoma, preoperatively staged as stage I or II, were investigated. After opening the thorax and before manipulation or palpation of the lungs, 300 ml of physiological saline solution was installed into the pleura. After excluding patients who were not radically operated, there remained 138 patients with histologically confirmed lung cancer (carcinoids excluded) and 12.3% showed tumour cells in the washings. Two of 18 patients with metastatic lung disease ( 11%) and one of ten patients with carcinoid tumor also showed malignant cells in the lavage. The patients with lung cancer have been followed for 3 years or until death. After three years 60.2% of those without malignant cells in the pleural lavage were still alive, while this figure was 41.2% in the other group. The difference was not statistically significant. Other factors, such as spread to local lymph nodes, size of tumor, etc. were related to the occurrence of malignant cells in the pleura, and these factors were also better prognostic ones. We conclude that the clinical use of pleural lavage cytology is limited.

Nonmalignant pleural disease related to asbestos exposure.

Asbestos and other mineral fibers are well known to cause pleural changes. These changes are of various types, the most common being pleural plaques, which are slowly growing and of little clinical importance. Other benign changes include asbestos pleurisies, rounded atelectases, and other pleuropulmonary changes.

Pleural and parenchymal fibrosis mainly affecting the upper lung lobes in persons exposed to asbestos.

From the County of Uppsala, Sweden, more than 1600 persons with pleural plaques and/or asbestos-related pleural thickening have been seen at the Uppsala University Hospital during a period of about 15 years. During the observation time, 40 patients developed lesions mainly affecting the upper lobes of the lung. They were all men, 41 to 78-years-old, and all had been occupationally exposed to asbestos. The mean latency time from the first exposure was 34 years. The mean width of the apical pleural thickening was 21 mm. In 21 patients the lesions were on the right side, in 15 they were bilateral, and in only four patients was the left side alone affected. Biopsies from the pleura were available in twelve patients and from the lung parenchyma in eight. The biopsies of the lungs all showed varying degrees of asbestosis and of the pleura nonspecific pleuritis. The lesions tended to progress and in all cases except one they were part of a diffuse pleural and parenchymal fibrosis involving the rest of the lung. Consequently, the pulmonary function was impaired, with the vital capacity reduced to an average of 62% and total lung capacity to 68% of the predicted value. In many patients there was contraction of the upper lobe and deviation of the trachea towards the same side. Upper lobe changes are a relatively rare complication of exposure to asbestos but are important to recognise. Other possible causes of upper lobe changes such as tuberculosis must always be excluded before the diagnosis is made.

Improved lung function and quality of life following increased elastic recoil after lung volume reduction surgery in emphysema.

Lung volume reduction surgery for severe emphysema with removal of 20-30% of the most destroyed parts of the lung parenchyma has been reported to improve lung function substantially. Increased elastic recoil has been suggested as one underlying mechanism for the improvement. Fourteen patients, seven men and seven women with a mean age of 62 years, who underwent bilateral lung volume reduction surgery have been followed up for 3 months. We here report the data on quality of life, lung function and elastic recoil. FEV1.0 increased by a mean of 26% from 0.581 to 0.731 (P < 0.01). The mean TLC was reduced by 16% from 8.91 to 7.51 (P < 0.001). The level of hyperinflation decreased as implied by a reduction in the ratio of RV to TLC from 0.70 to 0.60 (P < 0.001). The pulmonary elastic recoil improved, with an increase in the transpulmonary pressure at maximal inspiration (PelTLC) from 0.95 kPa to 1.35 kPa (P < 0.05) and an average increase in the coefficient of retraction PelTLC/TLC) from 0.12 kPa l-1 to 0.19 kPa l-1 (P < 0.01). The resting PaO2 increased from a mean of 8.7 kPa to 9.8 kPa (P < 0.01). The patients reported a high degree of subjective improvement according to the St. George's Respiratory Questionnaire and the working capacity on a bicycle increased by 26% from a mean of 38 W to 48 W (P < 0.01). The promising short-term results of lung volume reduction surgery for severe emphysema appear to be related to improved pulmonary elastic recoil.

The impact of pleurodesis in malignant effusion on respiratory function.

Pleurodesis of malignant pleural effusion provides for a substantially better quality of life compared to onging exudation with the need for repeated evacuation of fluid. Successful pleurodesis leads to permanent cessation of fluid production as a result of the formation of fibrous adhesion between the lung and costal pleura which in theory, however, might restrict lung mobility. In patients with poor lung function, or with need for bilateral pleurodesis, the apprehension of further impairment of lung function often arises. The aim of this study was to evaluate the effects of pleurodesis on lung function. Therefore 10 patients with malignant pleurisy with very limited tumour were investigated. They were without radiological signs of tumour infiltration in the lung parenchyma, without visible tumour growth in the pleural space during thoracoscopy and had undergone a successful one-sided pleurodesis. Respiratory function tests were performed at different times, 1-102 months after pleurodesis. The assessment consisted of: static and dynamic spirometry, exercise testing with blood gas determination and radiospirometry. Spirometric values were slightly low, but in general within the reference limits. Blood gas determination showed no signs of alveolar hypoventilation. Radiospirometry showed a slight attenuation of activity in the treated lung but similar turnover of gas of the treated vs. the untreated side. The study showed that pleurodesis in malignant pleurisy has only minor impact on respiratory function.

Environmental asbestos exposure and malignant pleural mesothelioma.

Asbestos-related benign and malignant pleural diseases are endemic in some rural parts of central Turkey because of environmental exposure to asbestos fibres. We report here epidemiological data on 113 patients with diffuse malignant pleural mesothelioma (DMPM) diagnosed in our clinic in Eskisehir, located in central Turkey. Of the 113 patients, 59 were men and 54 women (male:female ratio = 1). Ninety-seven patients (86%) had non-occupational asbestos exposure; all were living in villages. Their mean age was 56 years. As the patients had been exposed to asbestos from birth, the latency period was equivalent to the age of the patients. Twenty-eight patients (29%) had lived in villages their entire lives. The other 69 (71%) had been born in a village but migrated to the city or had given up white-soil usage for various reasons. The mean exposure time was 55 years for those with a long exposure period and 25 years for those with a short exposure period, but there was no significant difference between the age of the disease appearance for both groups (55 and 56 years, respectively). Thus, the latency time of mesothelioma due to environmental exposure to asbestos was longer than that due to occupational exposure, but independent of the length of exposure. Soil samples from 67 villages were analysed, comprising a population of 10,120 villagers. Tremolite and some other types of asbestos were found. In conclusion, DMPM in our region is due to mainly to environmental exposure to asbestos. The risk is substantial as a large proportion of the villagers are exposed. After smoking, asbestos exposure is one of the most serious health hazards in our rural population.

Asbestos-related radiographic changes by ILO classification of 10 x 10 cm chest X-rays in a screening of the general population.

A sample of 1388 10 x 10 cm chest X-rays from a previous population screening of males aged 40+ years were reevaluated by use of the ILO classification. There were 1036 films of subjects from an industrialized town, and 352 from a rural community. The observed rates of parenchymal changes (profusion > or = 1/0) at the reevaluation were 1.3% in the urban community and 3.4% in the rural community. The corresponding figures for pleural changes were 5.0% and 0.6%, respectively. Based on additional questionnaire information on asbestos exposure, it was found that the radiographic changes were probably related to past asbestos exposure for 2.3% of the subjects from the urban community and 0.6% from the rural community. In cases of asbestos-related illnesses the mean time since first exposure to asbestos was 35.9 years, whereas the mean duration of the exposures was 11.4 years. The results seem to indicate that the ILO reassessment of the radiographs was more sensitive in detecting pleural changes than the previous clinical screening of both small and large films.

Pleural changes and exposure to fibrous minerals.

The pleura is a main target for various reactions related to asbestos exposure. However there are great radiological and clinical differences between the various reactions, and there is also increasing evidence that they have different prognoses. The main reactions are pleural plaques on the one hand and acute pleurisy and diffuse pleural fibrosis on the other. In a population with a low mesothelioma risk, the anthophyllite-exposed population of Northern Karelia in Finland, there are very few reactions of the second type, while plaques are very common. In Turkey, where the exposure is to erionite, the mesothelioma level is extremely high, and reactions of type two are very common in the exposed population. Thus it seems that careful discrimination of the various pleural changes can have prognostic value. There are also indications that plaques do not have any relation to a disturbed immunologic system, while pleurisy and diffuse pleurisy have.

Asbestos, asbestosis, pleural plaques and lung cancer.

Inhalation of asbestos fibers increases the risk of bronchial carcinoma. It has been claimed that asbestosis is a necessary prerequisite for the malignancy, but epidemiologic studies usually do not have enough statistical strength to prove that asbestos-exposed patients without asbestosis are without risk. Several recent studies do actually indicate that there is a risk for such patients. In addition, case-referent studies of patients with lung cancer show an attributable risk for asbestos of 6% to 23%, which is much higher than the actual occurrence of asbestosis among these patients. Thus there is an increasing body of evidence that, at low exposure levels, asbestos produces a slight increase in the relative risk of lung cancer even in the absence of asbestosis. Consequently, all exposure to asbestos must be minimized.

Symptoms in heavy snorers with and without obstructive sleep apnea.

Five hundred and eighty persons who were heavy snorers filled in a questionnaire regarding symptoms on a 5-grade scale. Of these, 178 had a complete polysomnography investigation while 402 patients underwent oxymetric screening during the night only. On the basis of these investigations. 217 were classified as suffering from the obstructive sleep apnea syndrome (OSAS) and 363 as snorers without OSAS. The symptom scores differed between the two groups, but the range was wide and some persons with OSAS claimed only minor daytime sleepiness, somnolence, etc., while a high proportion of persons without OSAS frequently suffered from such symptoms. Thus, it was not possible to discriminate between patients with and without OSAS on the basis of their symptoms only. Furthermore, there are many persons who are "only" heavy snorers but who have symptoms that affect their career and social life and who so far have only received scant interest from the medical profession. Excessive daytime sleepiness and somnolence thus do not seem to be secondary to hypoxemia at night but rather to poor quality of sleep, which may be the case in association with heavy snoring even without appreciable deterioration of oxygen saturation.

Laryngeal edema as the only symptom of hypersensitivity to salicylic acid and other substances.

Idiosyncrasy to salicylic acid and related substances is well known, the most common symptoms being asthma, rhinorrhea and urticaria. We here describe two cases whose only symptoms were hoarseness and in which inspection revealed laryngeal edema when the patients ingested any of these substances. In cases of chronic recurring hoarseness, a history should be taken with respect to such hypersensitivity and suspect cases should be challenged, since a strict diet may improve the symptoms.