[Effect of tinzaparin on survival in non-small-cell lung cancer after surgery. TILT: tinzaparin in lung tumours]. / Effet de la tinzaparine sur la mortalité du cancer bronchique non à petites cellules opéré.

BACKGROUND: Experimental and clinical findings suggest that low molecular-weight heparins may improve overall survival in patients with cancer. The evidence is still limited and additional studies are needed to confirm these preliminary findings. METHODS: Patients with completely resected stage I, II or IIIA (T3N1) histologically confirmed non-small-cell lung cancer will be included in a prospective, controlled, randomized, multicenter open trial. Patients in the control group will receive usual postoperative care including chemotherapy when indicated. Patients in the experimental group will receive tinzaparin given subcutaneously as a daily 100 IU/kg dose for 90 days along with usual postoperative care. Patients will be followed-up for three to eight years. Main end-point is the overall survival. Five hundred and fifty patients are needed to demonstrate a 10% absolute increase in survival in the experimental group. EXPECTED RESULTS: A 10% absolute increase in the survival rate is expected in the patients receiving tinzaparin.

[Long-term survivors of advanced non-small-cell lung cancer: characterisation and prognostic factors in a retrospective study]. / Longs survivants de cancers bronchiques non à petites cellules stades IIIB-IV.

INTRODUCTION: The prognosis of non-small cell lung cancer (NSCLC) is poor, especially for advanced stages IIIB-IV. Clinical experience shows that the evolution of the disease is heterogeneous. A small number of patients survive more than 2 years after diagnosis; they are called long term survivors (LS). The aim of our study was to characterise this subgroup of patients. METHODS: A retrospective study in the respiratory department of a general hospital including all patients with a proven diagnosis of NSCLC stage IIIB and IV. RESULTS: 169 patients were included (43 females). There were 13.6% LS. Two thirds of the patients were PS 0-1, 84.6% were stage IIIBw-IV. Adenocarcinoma was the predominant histological type. Univariate analysis revealed that long term survival was associated with a Charlson's score < or = 2, PS 0-1, a normal white blood cell count at diagnosis, adenocarcinoma histology, response (RP) to first line treatment and treatment with a tyrosine-kinase inhibitor (TKI). In multivariate analysis only PS 0-1, RP and treatment with a TKI were independent factors for longer survival. CONCLUSION: LS exist and represent 13.6% of our patients. TKI appear to offer new opportunities for these patients.

[IFCT-0302 trial: randomised study comparing two follow-up schedules in completely resected non-small cell lung cancer]. / Protocole IFCT-0302: essai randomisé de deux schémas de surveillance dans les cancers bronchiques non à petites cellules complètement réséqués.

BACKGROUND: The authorities advocate a minimalist attitude towards the follow-up of resected bronchial carcinoma (clinical examination and chest x-ray). A survey showed that 70% of French respiratory physicians have chosen to use the CT scanner and often endoscopy. The published data are equivocal and are often based on retrospective studies. Lung cancer is a good model for a study of post-operative surveillance. Recurrences often occur in easily observed areas, they may be detected while still asymptomatic and are sometimes potentially curable. Second primary tumours may develop at the same site. METHODS: The Intergroupe Francophone de Cancerologie Thoracique (IFCT) has initiated a trial comparing simple follow-up (clinical examination, chest x-ray) with a more intensive follow-up (CT scan, fibreoptic bronchoscopy). The surveillance will take place every 6 months for 2 years and then annually until 5 years. EXPECTED RESULTS: The main aim is to determine whether intensive follow-up improves patient survival. The opposite question is equally important. If an expensive and demanding follow-up does not affect the chances of cure these results will influence our practice.

[Lung cancer in the elderly: performance status and/or geriatric indices?]. / Cancer bronchique du sujet âgé: performance status et/ou indices gériatriques?

INTRODUCTION: Demographic aging poses a problem of management in patients over 65 years old with lung cancer (LC). Performance status (PS) is an index of global activity that, in part, determines treatment. Geriatric indices allow a multifactorial assessment of the elderly subject. The aim of our study is to evaluate whether PS correlates with the geriatric indices in elderly patients with lung cancer. METHODS: In a single centre prospective study the geriatric indices (ADL, IADL, PINI, MMS) and the Charlson score (CS) were measured before treatment. RESULTS: Forty one patients aged 75.7 +/- 6.6 years were included in the study. PS 3-4 was found in 15% of patients and 44% had stage IV disease. Half of them were ADL dependent and 95% were IADL dependent. A MMS<24 was found in 29% and 17% had a PINI > 20. The CS was 2.7 +/- 2.1. There was a correlation between PS and the geriatric indices but no correlation between PS and CS. CONCLUSION: PS is significantly correlated with the geriatric indices but is independent of CS. PS appears to be a good parameter for the assessment of global activity in the elderly subject with LC.

[Primary non-small-cell lung cancer: analysis of 419 T1 (

T1 tumors have the best prognosis among primary non-small-cell lung cancers, basically because surgery is generally possible. Among 5.667 patients with primary lung cancer included in the KBP-2000-CPHG study, we examined the characteristics of 419 T1 tumors, i.e. 9.2% of the non-small-cell cancers. Compared with the group of patients with non-T1 tumors, patients with T1 tumors were younger (p=0.0007). They had an equivalent percentage of squamous-cell tumors but more adenocarcinomas (40.3% versus 35.5%, p=0.05). TNM staging showed that 27.6% of the T1 tumors were metastatic at diagnosis (stage IV) with 12.4% T1N0M1 nad 15.2% T1N1-3M1. For the M0 tumors, 52.2% were T1N0 (stage IA) and 20.1% were T1N1-3. Squamous-cell tumors were significantly more frequent among the T1M1 tumors (p=0.07). More than one quarter (27.6%) of the T1 tumors were in stage IV, pointing out the importance of the initial work-up. This findings suggests we should revisit strategies in order to take into account new diagnostic possibilities. Likewise for the therapeutic strategy. Combinations using chemotherapy, surgery and radiotherapy should be better defined for this group of tumors.

[Gastric volvulus associated with Zenker's diverticulum: a rare cause of recurrent pneumopathy]. / Volvulus gastrique associé à un diverticule de Zenker: une cause rare de pneumopathie récidivante.

We report on a case of a patient with recurrent pneumonia related to a pharygo-esophageal (Zenker's) diverticulum associated with a chronic thoracic gastric volvulus. Mechanism, diagnosis and treatment of this rare disease are discussed.

[Mycoplasma pneumoniae pneumopathy. 10 cases]. / Pneumopathie à Mycoplasma pneumoniae. 10 observations.

OBJECTIVES: Describe the different features of a common disease: Mycoplasma pneumoniae pneumonia. PATIENTS AND METHODS: The hospital files of 10 consecutive patients with microbiologically proven Mycoplasma pneumoniae pneumonia were reviewed retrospectively. These 10 patients were hospitalized over a 15-month period among 150 patients admitted to the Versailles general hospital for community-acquired pneumonia. We compared our series with data in the literature. RESULTS: Most of the patients with Mycoplasma pneumoniae pneumonia were young apparently healthy adults. A bronchial risk factor (smoking, allergy) was however found in 60% of the patients. The principle symptom was persistent cough (100%), with fever and joint pain, or sometimes headache and signs of ENT involvement. Dyspnea was frequent, related more to associated bronchospasticity than to the severity of the pneumonia. Radiographic findings were quite variable. In one case hemolytic anemia and cold agglutinins suggested the diagnosis. Certain diagnosis was based on positive serology after hospitalization due to the long delay between symptom onset and hospitalization. The prehospital period was characterized by a succession of ineffective empirical antibiotic regimens. In routine practice, macrolides or fluoroquinolones administered for 2 to 3 weeks are the empirical antibiotics of choice. Outcome is generally favorable with rapid clinical and radiological improvement. Antibiotic therapy is not however sufficient alone to achieve improvement in the respiratory impairment: bronchodilators and corticosteroids are necessary to treat the bronchospasticity. CONCLUSION: Despite the benign nature of community-acquired pneumonia due to Mycoplasma pneumoniae, clinical manifestations, particularly bronchial inflammation may have important consequences.

[Pulmonary embolism. Risk factors of venous thromboembolic disease]. / Embolie pulmonaire. Facteurs de risque de la maladie thrombo-embolique veineuse.

RISK FACTORS: Management of deep venous thromboembolism both in terms of diagnosis and therapeutic and prophylactic strategies has been greatly improved by advances in knowledge of the main acquired and intrinsic risk factors. RESISTANCE TO ACTIVATED PROTEIN C: This is by far the most frequent coagulation disorder predisposing to venous thromboembolism. Other intrinsic factors favoring thrombus formation (anti-thrombin II, protein C or protein S deficiencies) are much more uncommon. Laboratory tests in search for these anomalies are indicated essentially for patients who develop repeated episodes of venous thrombus formation. PROPHYLAXIS: Excepting specific cases, anticoagulant prophylaxis is not indicated in any of these anomalies beyond the usual treatment of a first episode. Among the risk factors for acquired deep vein thromboembolism, only surgery and certain obstetrical indications have been investigated sufficiently to define validated prophylaxis strategies. For medical risks, the benefit of anticoagulant prophylaxis has been demonstrated in certain disease states such as cancer, antiphospholipid syndrome and the acute phase of myocardial infarction although no widely accepted strategy has yet been established.

A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire.

BACKGROUND: Low-molecular-weight heparin appears to be at least as effective and safe as standard, unfractionated heparin for the treatment of deep-vein thrombosis, but only limited data are available on the use of low-molecular-weight heparin to treat acute symptomatic pulmonary embolism. METHODS: We randomly assigned 612 patients with symptomatic pulmonary embolism who did not require thrombolytic therapy or embolectomy to either subcutaneous low-molecular-weight heparin (tinzaparin) given once daily in a fixed dose or adjusted-dose, intravenous unfractionated heparin. Oral anticoagulant therapy was begun between the first and the third day and was given for at least three months. We compared the treatments at day 8 and day 90 with respect to a combined end point of recurrent thromboembolism, major bleeding, and death. RESULTS: In the first eight days of treatment, 9 of 308 patients assigned to receive unfractionated heparin (2.9 percent) reached at least one of the end points, as compared,with 9 of 304 patients assigned to low-molecular-weight heparin (3.0 percent; absolute difference, 0.1 percentage point; 95 percent confidence interval, -2.7 to 2.6). By day 90, 22 patients assigned to unfractionated heparin (7.1 percent) and 18 patients assigned to low-molecular-weight heparin (5.9 percent) had reached at least one end point (P=0.54; absolute difference, 1.2 percentage points; 95 percent confidence interval, -2.7 to 5.1). The risk of major bleeding was similar in the two treatment groups throughout the study. CONCLUSIONS: Under the conditions of this study, initial subcutaneous therapy with the low-molecular-weight heparin tinzaparin appeared to be as effective and safe as intravenous unfractionated heparin in patients with acute pulmonary embolism.

Lung perfusion scans and hemodynamics in acute and chronic pulmonary embolism.

UNLABELLED: To assess the relationship between pulmonary vascular obstruction and hemodynamic status in acute pulmonary embolism (APE) and in chronic thromboembolic pulmonary hypertension (CTEPH), perfusion lung scan and hemodynamic measurements were obtained in 31 consecutive patients with APE and in 45 with CTEPH. METHODS: Lung scans were scored independently by two experience observers who determined the percentage of vascular obstruction (PVOs). Mean pulmonary artery pressure (PAP) and total pulmonary resistance (TPR) were obtained during right heart catheterization. In patients with APE, measurements were recorded within a 1-hr interval before and 12 hours after thrombolysis. This yielded 62 paired PVOs values with concomitant PAP and TPR measurements. In patients with CTEPH, data were recorded within a 3-day interval. RESULTS: Mean PVOs (%) values were similar in APE and CTEPH patients (59 +/- 13 vs. 58 +/- 15), whereas PAP and TPR were significantly higher in CTEPH patients (51 +/- 17 mmHg and 23 +/- 11 U/m2, respectively) than in APE patients (23 +/- 8 mmHg and 9 +/- 5 U/m2, respectively, p < 0.001). In APE patients, significant hyperbolic correlations were found linking PVOs with PAP and TPR (r = 0.75, p < 0.01 for PAP; r = 0.71, p < 0.01 for TPR). In CTEPH, there were no significant correlations between PVOs and PAP or TPR. For the same level of PVOs, patients with CTEPH had higher PAP and TPR value than patients with APE. CONCLUSION: In APE without prior cardiopulmonary disease, increases in PAP and TPR are correlated in a nonlinear fashion with the degree of pulmonary vascular obstruction as assessed by lung scanning. In CTEPH patients, the higher PAP and TPR values as compared to APE patients with comparable degrees of PVOs are consistent with previous reports that pulmonary hypertension in CTEPH is due not only to the obstruction of proximal pulmonary arteries but also to remodeling of small distal arteries in nonoccluded areas.

Clinical significance of the pulmonary vasodilator response during short-term infusion of prostacyclin in primary pulmonary hypertension.

BACKGROUND: The short-term vasodilator response to prostacyclin (PGI2) in patients with primary pulmonary hypertension (PPH) is not only unpredictable but also extremely variable in magnitude. In this retrospective study, we attempted to evaluate in a nonselected population of patients with PPH the degree of vasodilatation achieved during short-term infusion of PGI2 and to investigate whether patients with PPH differed in terms of baseline characteristics and prognoses, according to the level of vasodilatation achieved during initial testing with PGI2. METHODS AND RESULTS: Between 1984 and 1992, 91 consecutive patients with PPH underwent catheterization of the right side of the heart with a short-term vasodilator trial with PGI2 (5 to 10 ng.kg-1.min-1). According to the level of vasodilatation achieved during PGI2 infusion, patients were divided into three groups: nonresponding (NR, n = 40), moderately responding (MR, n = 42), and highly responding (HR, n = 9) patients. All three groups were defined by a decrease in total pulmonary resistance index (TPRi) of < 20%, between 20% and 50%, and > 50%, respectively, relative to control values. Prolonged oral vasodilator therapy was subsequently started only in MR and HR patients. All patients had long-term oral anticoagulant therapy. The survival rate at 2 years (transplant recipients excluded) was significantly higher in HR patients compared with NR and MR patients (62% versus 38% and 47% survivors, respectively; P < .05). Comparisons between groups showed no significant differences in baseline hemodynamics or clinical characteristics except for a longer time between onset of symptoms and diagnosis (ie, first catheterization) of PPH in HR patients than in NR and MR patients (71 +/- 61 versus 35 +/- 34 and 21 +/- 21 months, respectively; P < .05). CONCLUSIONS: In this study, patients with PPH exhibiting a decrease in TPRi > 50% during short-term PGI2 challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response.

[Chronic pulmonary heart disease: therapeutic indications]. / Coeur pulmonaire chronique postembolique. Indications thérapeutiques.

Chronic thromboembolic cor pulmonale is a serious condition and its frequency seems to be on the increase. The authors report their personal experience of 100 cases and review the literature to describe the natural history, diagnostic strategy and therapeutic indications of this condition. The mechanisms of this aberrant evolution of acute pulmonary embolism are unknown. They key symptom is effort dyspnea without a ventilatory deficit. The most useful diagnostic investigations are Doppler echocardiography and perfusion pulmonary scintigraphy. The diagnosis is confirmed by pulmonary angiography which, with the aid of a thoracic CT scan or endovascular techniques (ultrasonography or angioscopy), allow assessment of the feasibility of thromboendarteriectomy. Medical treatment is based on long-term anticoagulation, in some cases of lower limb thrombosis associated with interruption of the inferior vena cava. Two possible curative surgical techniques are available in selected patients; thromboendarteriectomy and pulmonary transplantation, the relative indications of which are listed. Of all the causes of pulmonary hypertension, chronic thromboembolic cor pulmonary should be systematically looked for because curative surgical treatment is possible in some cases.

Lipopolysaccharides stimulate Na-dependent transport in alveolar cells and protect against oxidant injury.

We have evaluated the effect of lipopolysaccharides (LPS), endotoxins from gram negative bacteria, on sodium-coupled amino acid and phosphate transport by alveolar epithelial type II cells and on their alteration induced by oxidants. Alveolar type II cells were obtained by enzymatic digestion of rat lung and grown for 24 h prior to incubation with LPS and then exposed or not exposed to H2O2 (2.5 mM; 20 min). LPS (10 micrograms/ml, 24 h) induced a significant increase in the Na-dependent component of alanine and phosphate uptake while they decreased Na,K-ATPase activity measured by ouabain-sensitive 86Rb influx. We showed that this stimulatory effect i) was independent from macrophage products since it was not mimicked either by supernatant of LPS-treated alveolar macrophages or by pretreatment with tumor necrosis factor and/or interleukin 1 and ii) was dependent on protein synthesis since it was abolished by protein synthesis inhibitors cycloheximide and actinomycin D. Moreover, LPS blunted H2O2-induced decrease of Na-dependent alanine and phosphate uptake. This protective effect of LPS against H2O2 injury i) was independent of macrophage products, ii) was abolished by cycloheximide, and iii) was not associated with either changes in extracellular H2O2 clearance or catalase and glutathione peroxidase activities. We conclude that, in alveolar type II cells, LPS stimulate sodium-coupled transport by a process involving protein synthesis and partially prevent H2O2-induced decrease of Na-coupled transport without discernible change in antioxidant activities.

Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin.

To investigate the capacity of the pulmonary vascular bed to acutely vasodilate, we examined in 35 consecutive patients with primary pulmonary hypertension (PPH), the hemodynamic effects of incremental inhalation periods of an air-NO mixture at different concentrations (10, 20, and 40 ppm), and compared them with those of an acute infusion of prostacyclin (PGI2). An individual pulmonary vasodilator response was defined by a fall in total pulmonary resistance (TPR) > or = 30% relative to mean TPR baseline value. Thirteen patients were responders and 22 were nonresponders to both drugs, and they did not significantly differ in overall baseline characteristics except for mean right atrial pressure (p < 0.03). In responders, both drugs produced similar individual vasodilator response. Changes in mean pulmonary arterial pressure and TPR observed during NO and PGI2 were closely correlated (r2 = 0.9, p < 0.001, and r2 = 0.7, p < 0.01, respectively). The vasodilator response to NO was not concentration-related with a maximal effect obtained at 10 ppm. Combination of both drugs did not lead to any additive vasodilator response. Unlike PGI2, NO did not induce any systemic effect, no adverse reaction, but a moderate increase in methemoglobin. Inhaled NO at low dose (10 ppm) appears to be an effective, safe, and reliable substitute for PGI2 in screening for acute pulmonary vasodilator responsiveness during therapeutic assessment of patients with PPH.

Surgical management of unresolved pulmonary embolism. A personal series of 72 patients.

Chronic thromboembolic pulmonary hypertension (CT-E PH) is a rare and aberrant outcome of acute pulmonary embolism. Because it has become a potentially curable form of pulmonary hypertension, the frequency of recognized cases has increased. We report a case series of 72 patients with CT-E PH evaluated in our institution between 1984 and 1993, and discuss diagnostic clues and therapeutic approaches. All patients complained of dyspnea on exertion, a history of acute thromboembolic event, and lung murmurs were found in 60% and 17% of patients, respectively. The presence of a disorder of coagulation was found in 30% of the patients tested, the most common abnormality being lupus anticoagulant. The key noninvasive study for diagnosis was the lung perfusion scan which showed at least one segmental or larger perfusion defect in all patients. Pulmonary angiography confirmed the diagnosis in all cases, and sometimes associated to intravascular ultrasound imaging, established the feasibility of thromboendarterectomy. Medical therapy included the use of long-term oral anticoagulant, and in the case of lower limb venous thrombosis, inferior vena cava filtration. Finally two surgical procedures were discussed in selected patients: thromboendarterectomy and lung transplantation. Since 1988, eight patients have benefited from lung transplantation (six patients are still alive), and 11 patients underwent thromboendarterectomy which was successful in 9 patients with a dramatic functional and hemodynamic improvement.

[Pulmonary arterial hypertension of chronic thromboembolic origin; therapeutic indications]. / Hypertension artérielle pulmonaire d'origine thrombo-embolique chronique; indications thérapeutiques.

Chronic thromboembolic pulmonary hypertension is a rare complication of acute pulmonary embolism. The therapeutic approach to the disease is addressed, based on a series of 81 patients referred to our department between 1984 and 1993. Medical treatment associates long-term anticoagulant therapy and, in some cases, inferior vena cava interruption. Two surgical procedures are available in selected patients: lung transplantation and pulmonary thrombo-endareterectomy. Lung transplantation has been performed in 8 patients since 1988 with 6 survivors with a maximal follow-up of 5 years. Twelve patients underwent pulmonary thromboendareterectomy with in 9 patients a dramatic functional and haemodynamic improvement. Chronic thromboembolism should be systematically investigated as the cause of pulmonary hypertension considering that in selected cases, curative surgery is possible.