Chrysotile and tremolite asbestos fibres in the lungs and parietal pleura of Corsican goats.

BACKGROUND AND AIMS: Environmental exposures to chrysotile and tremolite from the soil cause pleural plaques and mesothelioma in northeast Corsica. Goats grazing in the contaminated areas inhale asbestos fibres. We used this natural animal model to study whether these exposures actually result in increased fibre burdens in the lungs and parietal pleura. METHODS: Ten goats from areas with asbestos outcrops and two from other areas were slaughtered. Fibre content of lung and parietal pleural samples was determined by analytical transmission electron microscopy. RESULTS: Both chrysotile and tremolite fibres were detected. In the exposed goats, the geometric mean concentrations of asbestos fibres longer than 1 microm were 0.27 x 10(6) fibres/g dry lung tissue and 1.8 x 10(6) fibres/g dry pleural tissue. Asbestos fibres were not detected in the lungs of the two control goats. Chrysotile fibres shorter than 5 microm were predominant in the parietal pleura. Tremolite fibres accounted for 78% and 86% of the fibres longer than 5 microm in lung and parietal pleural samples, respectively. CONCLUSIONS: Environmental exposure in northeast Corsica results in detectable chrysotile and tremolite fibre loads in the lung and parietal pleura of adult goats. Tremolite fibres of dimensions with a high carcinogenic potency are detected in the parietal pleura.

[Malignant pleural effusions: recourse to early use of talc]. / Epanchements pleuraux malins: le recours précoce au talcage.

INTRODUCTION: Our purpose was to assess the efficacy, permanence and safety of thoracoscopic talc poudrage (TTP) for pleurodesis in malignant effusions. We report the follow-up of 360 patients who received TTP in two centers in Marseille (France). CURRENT KNOWLEDGE AND KEY POINTS: Eighty-eight patients presented with mesothelioma and 272 had pleural metastasis. The mean follow-up time was 12 months (range: 2-120). Out of the 327 patients whose response could be evaluated, 90.2% had a successful pleurodesis at 1 month, and 82.1% had a life-long pleural symphysis. Adverse effects included one death 3 days after the procedure in an end-stage patient, fever (9.8%), infection of the parietal scar (2.5%) and pulmonary infection (0.8%). FUTURE PROSPECTS AND PROJECTS: TTP is an effective and safe method of life-long pleurodesis. It should be performed early on in the history of malignant effusions to avoid failures of the technic, mainly linked to trapped lung and to the general condition of patients.

Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: a Phase II study.

BACKGROUND: The prognosis associated with malignant pleural mesothelioma (MPM) is poor in spite of surgery, radiotherapy, photodynamic therapy, or chemotherapy. Therefore, new therapeutic strategies, including intrapleural immunotherapy, are being investigated. Several clinical studies have demonstrated objective antitumoral responses to intrapleural interleukin-2 (IL-2) administration in the treatment of malignant pleurisy. The maximum tolerated dose, 24 x 10(6) IU/m2/day for 5 days, was determined in a Phase I study. Based on these results, a Phase II study was conducted, in which intrapleural IL-2 (21 x 10(6) IU/m2/day for 5 days) was given to patients with MPM. METHODS: Patients with histologically documented MPM were evaluated for response 36 days after treatment by computed tomography scan and thoracoscopy with biopsies. Toxicity was recorded and graded according to World Health Organization criteria. Survival was calculated from the start of treatment to death according to the Kaplan-Meier method, and the survival of responders and nonresponders was compared using the log rank test. RESULTS: Twenty-two patients entered this study. Of the 22 cases of MPM, 19 were epithelial, 2 were mixed, and 1 was fibrosarcomatous. Three patients had Stage IA disease, 1 had Stage IB, 16 had Stage II, 1 had Stage III, and 1 had Stage IV (Butchart classification). All patients received their planned treatment. No dose reduction or interruption occurred. There were 11 partial responses and 1 complete response. Stable disease occurred in 3 patients and disease progression in 7 patients. The overall median survival time was 18 months; the median survival time of responders differed significantly from that of nonresponders (28 months vs. 8 months, P < 0.01). The 24- and 36-month survival rates for responders were 58% and 41%, respectively. CONCLUSIONS: These results confirm that intrapleural administration of IL-2 is well tolerated and has antitumor activity in patients with MPM. The authors recommend a dose of 21 x 10(6) IU/m2/day for 5 days. However, determination of the schedule of IL-2 and its superiority to conventional treatment in a Phase III study has yet to be accomplished.

Cisplatin, ifosfamide, and vinorelbine combination chemotherapy in stage III-IV non-small-cell lung cancer: a phase II study.

The authors evaluate the combination of three drugs, vinorelbine, ifosfamide, and cisplatin, which have been shown to produce good response rates and a significant gain in survival when any two of them are given together. Seventy-seven untreated patients with inoperable stage III-IV non-small-cell lung cancer from three centers were included. The combination consisted of cisplatin 30 mg/m2 daily, ifosfamide 1,500 mg/m2 daily, mesna 1,500 mg/m2 daily on days 1-3, and vinorelbine 25 mg/m2 daily on days 1 and 8. Four cycles were administered every 4 weeks for a total of 267 cycles, before an assessment for toxicity, effective dose intensity, response rate, and survival was made. Toxicity was mainly hematologic (grade 3-4 neutropenia (15.7%), anemia (8.2%), and thrombopenia (2.6%)) but did not require granulocyte colony-stimulating factors. Objective response rate was 41.1% (95% confidence interval, 29.5-52.9%) in 68 patients suitable for assessment. The mean time to progression and median survival were 7.7 +/- 1.3 months and 11.6 months, respectively. One-year survival was 47.1%. The effective dose intensity of cisplatin and ifosfamide correlated strongly with survival, whereas stage and performance status did not. This study confirms previously reported favorable results for response and survival rates obtained in stage III-IV non-small-cell lung cancer with the vinorelbine, ifosfamide, and cisplatin combination. Respect of a scheduled dose intensity has a clear-cut influence on survival and should be evaluated routinely in future polychemotherapy trials.

[Malignant pleural mesothelioma in 1997]. / Le mésothéliome pleural malin en 1997.

Some recent data on malignant pleural mesothelioma are reviewed, viz. the French 1996 INSERM report, our mineralogic study of anthracotic parietal pleura, and the new TNM classification of the International Mesothelioma interest Group (I.M.I.G.). Among medical treatments, intrapleural immunotherapy achieves the best objective responses in early stage mesothelioma. Radiotherapy alone has little effect on advanced mesothelioma. By contrast, recent surgical series have shown better survival rates and underline the interest of the new TNM staging. Finally, malignant pleural mesothelioma behaves something like lung cancer, in that only in N- stages can prolonged survivals be expected.

Thoracoscopic talc poudrage pleurodesis for malignant effusions. A review of 360 cases.

OBJECTIVE: To assess the efficacy, permanence, and safety of thoracoscopic talc poudrage (TTP) for pleurodesis in malignant effusions. DESIGN: Retrospective. PARTICIPANTS: Patients with lifetime follow-up who received TTP in two related centers in Marseilles, France. RESULTS: Three hundred sixty patients were included in this study: 88 had mesothelioma and 272 had pleural metastases. The mean follow-up time was 12 months (2 to 120). Of the 327 patients whose response could be evaluated, 90.2% had a successful pleurodesis at 1 month, and 82.1% had a life-long pleural symphysis. Adverse effects included 1 death 3 days after the procedure in a patient with end-stage disease, fever (9.8%), empyema (2.5%), pulmonary infection (0.8%), and malignant invasion of the scar (1 patient). CONCLUSIONS: TTP is an effective and safe method of lifelong pleurodesis. It should be performed early on in the history of malignant effusions to avoid the risk of respiratory failure, this being directly linked to the general and respiratory status of the patients at the time of the procedure.

Black spots concentrate oncogenic asbestos fibers in the parietal pleura. Thoracoscopic and mineralogic study.

Epidemiologic and pathologic data demonstrate that malignant mesothelioma occurs preferentially after exposure to long amphibole asbestos fibers. However, mineralogic studies have rarely detected such fibers in the parietal pleura. We hypothesized that the distribution of asbestos fibers in the pleura was heterogeneous and that they might concentrate in certain areas, as does coal dust in patients showing anthracotic "black spots" of the parietal pleura during thoracoscopy. We collected thoracoscopic biopsy samples from these black spots and from normal areas of the parietal pleura and lung from 14 subjects (eight with and six without asbestos exposure). Asbestos content was determined by transmission electron microscopy. In exposed subjects, mean fiber concentrations were 12.4 +/- 9.8 x 10(6) fibers/g of dry tissue in lung, 4.1 +/- 1.9 in black spots, and 0.5 +/- 0.2 in normal pleura. In unexposed patients, concentrations were 0, 0.3 +/- 0.1, and 0, respectively. Amphiboles outnumbered chrysotile in all samples. A total of 22.5% of fibers were > or = 5 microns in length in black spots. A histologic similarity of these black spots with milky spots is suggested by conventional and electron microscopy. We conclude that the distribution of asbestos fibers is heterogeneous in the parietal pleura. Indeed, the fibers concentrate in black spots, where they can reach high concentrations. These findings could explain why the parietal pleura is the target organ for mesothelioma and plaques.

Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy.

The purpose of this randomized prospective study was to assess the efficacy of local radiotherapy in preventing malignant seeding along invasive diagnostic procedures (cytology, needle biopsy, thoracoscopy, or chest tube placement) in patients with malignant pleural mesothelioma. Forty consecutive patients with histologically proven malignant mesothelioma were enrolled. Twenty patients received three daily sessions of radiotherapy at a dosage of 7 Gy 10 to 15 days after thoracoscopy. The other 20 patients did not receive radiotherapy. None of the 20 patients treated developed entry tract metastasis. In contrast, 8 of the 20 (40%) patients who were not treated developed metastases. These findings confirm the efficacy and safety of early local radiotherapy in preventing malignant seeding after invasive diagnostic procedures in patients with malignant pleural mesothelioma.

Implantable access system for prolonged intrapleural immunotherapy.

We describe our experience using an implantable Port-A-Cath access system for intrapleural administration of gamma-interferon (gamma-IFN) in malignant mesothelioma patients. Twenty nine patients, with histologically proven malignant mesotheliomas were included in this study. To avoid complications the device was implanted in a subcutaneous pocket, and the catheter was connected via a tunnel. Also, a suction drain was installed in the pocket after placement. This procedure greatly reduced the high infection rate (64%) encountered with conventional open chest tubes. Patients' tolerance was excellent and maintenance minimal. In our opinion, the Port-A-Cath system is the most suitable device for intra-cavitary long-term therapy of malignant pleural effusions.

Environmental asbestotic pleural plaques in northeast Corsica: correlations with airborne and pleural mineralogic analysis.

We report a prevalence study of environmental pleural plaques in subjects over 50 years old from the northeastern Corsican village of Murato, built on asbestos surface deposits. The percentage of plaques was 41%, versus 7.5% in the control village of Vezzani. Although surface deposits contain both chrysotile and tremolite, airborne pollution and asbestos lung burden of exposed inhabitants consist essentially of tremolite as assessed by transmission electron microscopy (TEM). However, TEM analysis of the parietal pleura of three animals bred in exposed areas showed a predominance of short fibers of chrysotile. The respective roles of tremolite and chrysotile in inducing pleural plaques in Corsica should thus be considered.

[Epileptic seizures and treatment with ifosfamide-mesna]. / Crises épileptiques et traitement par ifosfamide-mesna.

Generalized and partial seizures with secondary generalization were observed during ifosfamide-mesna (IFO) treatment in a patient with lung epidermoid carcinoma. Seizures appeared in a stereotyped manner on the 3rd of the 4th and 6th day of treatment with IFO. Partially resolutive confusion was observed after the last cure. Brain CTS were normal. The responsibility of IFO is considered in the development of these neurological toxic manifestations.

Environmental pleural plaques in an asbestos exposed population of northeast Corsica.

The purpose of this study was to determine whether the inhabitants of villages environmentally exposed to asbestos, in northeast Corsica, had a higher incidence of pleural plaques. X-rays were obtained from subjects aged over 50 yrs, with no occupational exposure to asbestos or history of pleural disease, in one village exposed to asbestos, Murato, and a nonexposed, control village, Vezzani. In addition, the mineral content of the air and parietal pleura of animals in the exposed zone was studied, using transmission electron microscopy. The incidence of bilateral pleural plaques in the exposed population was 41%, as compared to 7.5% in the nonexposed population (p < 0.00001). The levels of airborne tremolite were higher in Murato (6-72 ng.m-3) than in Vezzani (< 1 ng.m-3), but chrysotile levels were similar. Significant numbers of chrysotile and tremolite fibres were identified in the parietal pleura of animals from the exposed village. This study confirms the well-known correlation between bilateral pleural plaques and environmental exposure to low levels of asbestos.

Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 2: Prognosis and staging.

BACKGROUND: Thoracoscopy appears to be essential in identifying tumors at the beginning of pleural disease. METHODS: Between 1973 and 1990, diagnostic thoracoscopy was carried out in a prospective series of 188 patients with malignant pleural mesothelioma (MPM). Biopsy samples were obtained in all cases, and diagnosis was confirmed by the French panel of mesothelioma specialists. In all patients we noted the degree of involvement of the parietal, diaphragmatic, or visceral pleura, and classified patients according to the Butchart system: Stage I (66 patients), II (110 patients), III (4 patients), and IV (8 patients). To assess prognostic factors, a multivariate analysis of clinical and endoscopic findings was performed according to the Cox model. RESULTS: The most favorable factors were absence of weight loss at the time of diagnosis, absence of involvement of the visceral pleura, Butchart Stage I, and epithelial histopathologic type. When Stage I patients were subdivided into two groups according to whether or not they displayed involvement of the visceral pleura, a significant difference in survival was noted (32.7 months versus 7 months, respectively; P < 0.001). CONCLUSIONS: Based on these findings, we propose to divide Butchart or Mattson Stage I into two subgroups, i.e., Stage IA in which only the parietal or diaphragmatic pleura is involved and Stage IB in which the visceral pleura is invaded. In the International Union Against Cancer (UICC) classification, T1 should be used for tumors restricted to the parietal or diaphragmatic pleura and T2 for tumors with additional involvement of the visceral pleura.

Intrapleural immunotherapy with escalating doses of interleukin-2 in metastatic pleural effusions.

BACKGROUND: The authors assessed the tolerance and efficacy of intrapleural interleukin-2 (IL-2) in patients with malignant effusion. METHODS: Twenty-three patients had a total of 25 metastatic pleural effusions; the patients were treated with recombinant IL-2 by means of a continuous intrapleural infusion for 5 days. The daily dosage used in this Phase I/II trial initially was 3 x 10(6) IU/m2/day; the dosage was increased with every third patient, culminating in a dosage of 24 x 10(6) IU/m2/day. RESULTS: One patient who had received the highest dosage died of renal failure on day 8. Ninety-six percent of patients had Grade 2-3 fever, which was easily controlled with paracetamol administration. Two (8%) patients had pleural empyema. All other side effects were mild and resolved spontaneously by the end of treatment. The objective response rate was 21.7%. The five patients who responded to IL-2 therapy were alive 7-24 months after treatment, and the survival rate of the whole group was 59% after 13 months. CONCLUSION: A daily dose of 10-24 x 10(6) IU/m2/day of IL-2 administered intrapleurally gave response rates similar to those reported in the literature using the intravenous route, but a much lower morbidity rate was recorded.

Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion.

The purpose of this phase 1 study was to determine the toxicity and effectiveness of recombinant interleukin-2 (RU 49637 Roussel Uclaf-France) administered by continuous pleural infusion for 5 days to patients with different histologic subtypes of pleural cancer. Incremental doses of rIL-2 from 3 x 10(6) to 24 x 10(6) were given via a thin catheter inserted into the homolateral pleural cavity. Patients were evaluated before treatment and 36 days after treatment by computed tomography scan and thoracoscopy with biopsy. Twenty-two patients with malignant pleural effusion (15 malignant pleural mesotheliomas, 6 adenocarcinomas, 1 squamous cell carcinoma) were treated. The maximum tolerated dose (MTD) of rIL-2, defined as the dose that produced grade 3 or greater toxic reactions in 50 percent of the patients, was 24 x 10(6) IU/m2/d. Although some side effects were encountered at any dose, tolerance was acceptable. The main side effect was fluid retention (8 of 22) which never exceeded 10 percent of body weight. Responses were achieved in 10 out of 22 patients with 1 complete remission (mesothelioma) and 9 partial remissions (3 adenocarcinomas and 6 malignant pleural mesotheliomas). Based on these results, we recommend that phase 2 studies using rIL-2 at a dose of 21 x 10(6) IU/m2/d via the intrapleural route be undertaken.

[Environmental mesotheliomas in northeast Corsica]. / Les mésothéliomes environnementaux en Corse du nord-est.

Since 1980, we have collected fourteen cases of mesothelioma induced by environmental exposure to asbestos, going back to childhood in patients from north-east Corsica, in a region which was remote from the asbestos mine of Canari. There were eight men and six women with a mean age of 69.5 +/- 4 years. Six patients presented with bilateral calcified pleural plaques as evidence of environmental exposure. The mineral analysis carried out on five patients (four had thoracoscopies and one an alveolar lavage), showed a moderate deposit of chrysotile (0.3 to 3.4 x 10(6) fibres per gram of dry tissue), and elevated level of tremolite (1.4 to 62 x 10(6) fibres/g). The ambient dosage of asbestos has confirmed the existence of environmental pollution by chrysotile fibres and above all by tremolite. In addition, the same type of fibres have been identified in the parietal pleural of animals subjected to the same risk. In this region, the risk is estimated, on the basis of our results, as 10 cases of mesothelioma per 100,000 inhabitants per year.

[Malignant mesothelioma: study of prognostic factors in a series of 188 cases]. / Mésothéliome malin: étude des facteurs pronostiques sur une série de 188 cas.

From 1973 to 1990, 188 patients with pleural malignant mesothelioma entered a prospective study of this disease to assess the main prognostic factors. All had undergone thoracoscopy with endoscopic description of lesions, and multiple biopsies. The diagnostic yield of thoracoscopy was 98.4%. Multivariate analysis of main clinical, histopathological, endoscopic and radiological (including CT-scan) parameters was performed according to Cox's model. The most favorable factors were: absence of weight loss at the time of diagnosis, absence of involvement of the visceral pleural, Butchart stage I and epithelial histopathological type. Thoracoscopy allowed early diagnosis of the disease and a subdivision of Butchart stage I into stage IA (with normal visceral pleura) and stage IB (with invaded visceral pleural): median survivals are 32.7 and 7 months respectively. Like CT scan, thoracoscopy is therefore necessary in the staging of malignant mesothelioma.

[Diseases of the pleura. Materials used and study technics]. / Exploration des maladies de la plèvre. Matériel utilisé et technique d'étude.

Pleural diseases frequently pose problems to the pulmonary physician. The clinical and radiological approaches are often insufficient and it is necessary to resort to techniques which enable a precise morphological diagnosis of the pleural lesion. Starting with a needle puncture and biopsy, the medical investigation of the pleura has been enriched by thoracoscopy which enables visualisation of not only the parietal and visceral pleura and the lung but also the mediastinum and the pericardium. Using this technique the diagnostic yield and the harmless nature of the technique are of the first importance. After recording traditional techniques of investigation of lung disease (puncture, needle biopsy) the equipment, the technique, the indications and the risks and the diagnostic results from thoracoscopy are discussed.