[Invasion of the pulmonary artery by an undifferentiated carcinoma]. / Obstruction tumorale de l'artère pulmonaire par un carcinome indifférencié

INTRODUCTION: The diagnosis of chronic obstruction of the pulmonary artery is difficult. We present the case of a woman with an invasive, undifferentiated carcinoma of the pulmonary artery. CASE REPORT: A 61 year old woman complained of increasing dyspnoea. This was evaluated by computed tomography which showed a defect in the main pulmonary artery. There was no clinical or radiological improvement following anticoagulant treatment for two months. A repeat CT scan showed a persisting intravascular defect and the diagnoses considered included post-embolic pulmonary arterial hypertension and angiosarcoma. A surgical biopsy was performed and pericardial and aortic tumour nodules were found during the operation. The pathological examination revealed undifferentiated carcinoma. Further investigations failed to reveal the primary site. CONCLUSION: Invasion of the pulmonary artery by angiosarcoma or other tumour is part of the differential diagnosis of chronic thromboembolic disease. The diagnosis rests on histology obtained by an intravascular or surgical procedure. Complete surgical excision may be possible in angiosarcoma but it was impossible in our patient. The patient died despite two courses of chemotherapy and targeted therapy with erlotinib.

Noninvasive ventilation reduces mortality in acute respiratory failure following lung resection.

When treated with invasive endotracheal mechanical ventilation (ETMV), acute respiratory insufficiency after lung resection is fatal in up to 80% of cases. Noninvasive positive-pressure ventilation (NPPV) may reduce the need for ETMV, thereby improving survival. We conducted a randomized prospective trial to compare standard therapy with and without nasal-mask NPPV in patients with acute hypoxemic respiratory insufficiency after lung resection. The primary outcome variable was the need for ETMV and the secondary outcome variables were in-hospital and 120-d mortality rates, duration of stay in the intensive care unit, and duration of in-hospital stay. Twelve of the 24 patients (50%) randomly assigned to the no-NPPV group required ETMV, versus only five of the 24 patients (20.8%) in the NPPV group (p = 0.035). Nine patients in the no-NPPV group died (37.5%), and three (12.5 %) patients in the NPPV group died (p = 0.045). The other secondary outcomes were similar in the two groups. NPPV is safe and effective in reducing the need for ETMV and improving survival after lung resection.

Factors affecting long-term survival after en-bloc resection of lung cancer invading the chest wall.

OBJECTIVE: Several reports emphasize the importance of en-bloc resection as the optimal surgical treatment of lung cancer with chest wall invasion. We investigated possible factors which could affect long-term survival following radical resection of these tumors. METHODS: Between 1981 and 1998, 100 patients (90 male; ten female), with a median age of 60 years (36-84), underwent radical en-bloc resection of non-small cell lung cancer (NSCLC) with chest wall involvement. Patients with superior sulcus tumors invading the thoracic inlet were excluded from this series. There were 43 squamous and 57 non-squamous tumors. The median number of resected ribs was three (1-5). Lung resection included 73 lobectomies, two bilobectomies, 18 pneumonectomies and seven segmentectomies. Chest wall resection also extended to the sternum in one patient, the transverse process in one, the costotransverse foramen and hemivertebrae in two. All patients had a complete resection. Sixty-three patients received postoperative radiotherapy and 12 received chemotherapy. Histological data, including differentiation and depth of chest wall invasion, were carefully reviewed. The effect of various factors on survival were studied. RESULTS: There were four in-hospital deaths. Lymph node involvement was negative on surgical specimens in 65 patients, and 28 patients had positive N1 nodes; the final histology revealed seven N2 diseases. Chest wall invasion was limited to the parietal pleura in 29 patients and included intercostal muscles, bones and extrathoracic muscles in 67, 24 and seven cases, respectively. The overall 2-year survival rate was 41%. The 5-year survival for patients with N0, N1 and N2 disease was 22, 9 and 0%, respectively. A local recurrence occurred in 13 patients, with four having a new resection and 45 patients developing systemic metastases. The nodal status (N0-1 vs. N2; P=0. 026) and the number of resected ribs(<2 vs. >2; P=0.03) were survival predictors in univariate analysis. By multivariate analysis, the two independent factors affecting long-term survival were the histological differentiation (well vs. poorly differentiated; P=0. 01) and the depth of chest wall invasion (parietal pleura vs. others; P=0.024). CONCLUSIONS: Histological differentiation and depth of chest wall involvement were the main factors affecting long-term survival in this series. The role of induction chemotherapy for tumors with poor prognosis should be investigated.

Expression and modulation of ICAM-1, TNF-alpha and RANTES in human alveolar macrophages from lung-transplant recipients in vitro.

Alveolar macrophages (AMs) play a central role in pulmonary inflammation in response to local stimuli. As a model for investigating anti-inflammatory drugs, we studied the effects of the cyclohexadepsipeptide antibiotic, fusafungine, and that of the glucocorticoid dexamethasone on the expression of ICAM-1, TNF-alpha and RANTES, induced in vitro by rIFN-gamma in human AMs freshly isolated from bronchoalveolar lavage fluid (BAL) obtained in lung-transplanted patients. ICAM-1 antigen expression, induced on AMs after 24 h of culture, was significantly inhibited by fusafungine in a concentration-dependent manner, as measured by flow cytometry analysis using an anti-CD54 monoclonal antibody. TNF-alpha production, but not RANTES release (measured by ELISA), was significantly inhibited. mRNA studies, by means of polymerase chain reaction amplification of complementary deoxyribonucleic acids (RT-PCR), showed no significant modification of mRNA levels, suggesting that fusafungine acts mainly at a post-transcriptional level. In the same conditions, dexamethasone significantly inhibited the release both of TNF-alpha and RANTES by AMs, mainly acting at the mRNA level, but had no effect on ICAM-1 expression. Assessment of the cellular and molecular targets of anti-inflammatory drugs in this model of human AM activation should lead to more appropriate treatment of inflammatory process of the respiratory tract. By virtue of its anti-inflammatory effects on alveolar macrophages, combined with its antibacterial properties, fusafungine should prove particularly suitable for local treatment of bacterial infections of the respiratory tract.

Aspergillus osteomyelitis after heart-lung transplantation.

Aspergillus osteomyelitis is a severe complication of invasive aspergillosis. Fewer than 15 cases have been observed after solid organ transplantation. We describe a case of Aspergillus osteomyelitis of the ilium after heart-lung transplantation with favorable outcome after medical treatment.

Expression of ICAM-1 and TNF alpha in human alveolar macrophages from lung-transplant recipients.

Local activation of macrophages may play an important role in the immune process of pulmonary infections and in the inflammatory response of lung allograft rejection. To document macrophage activation within human lung allografts displaying various complications, we have investigated ICAM-1 expression in freshly isolated alveolar macrophages (AM) from lung-transplant recipients by immunocytofluorimetric analysis, and rIFN gamma induced in vitro by ELISA. A total of 21 bronchoalveolar lavage fluids (BAL) from 13 transplanted patients displaying no complication, acute rejection, bacterial/fungal infection, or CMV infection entered the study. ICAM-1 was expressed at a higher level in rejecting patients. Surprisingly, TNF alpha release from AM upon in vitro activation was significantly decreased during rejection. Furthermore, we have studied the effects of the glucocorticoid dexamethasone, the key drug for the treatment of allograft rejection, on the expression of ICAM-1 and TNF alpha induced in vitro in AM, at the levels of protein production and of transcription. Whereas dexamethasone did not influence ICAM-1 expression in AM, it downregulated TNF alpha production at least in part at the transcriptional level. Our results suggest strongly that the anti-inflammatory effects of corticosteroids are not related to ICAM-1 modulation on human AM but to the downregulation of the proinflammatory cytokine TNF alpha that is produced early in the inflammatory process. Moreover, our model of human AM activation induced in vitro by rIFN gamma appears a useful tool for in vitro investigation of the cellular and molecular targets of anti-inflammatory drugs for a more appropriate use.

Prognostic significance of peritumoural blood and lymphatic vessel invasion by tumour cells in T4 non-small cell lung cancer following induction therapy.

We investigated the impact of new biological prognostic factors is in 28 patients receiving a median of two courses of cisplatin-based chemotherapy with (n = 14) or without (n = 14) radiation and operation for stage IIIB (T4) non-small cell lung cancer (NSCLC). After induction therapy, 5 patients had a complete and 21 a partial response; 2 had a stable disease. A complete resection was made in 26 patients (93%). Five patients (18%) had their primary tumour and involved vestiges completely sterilized. In the remaining 23, the majority of the tumours showed abnormalities in the p53 gene expression (56%), harboured proliferating cells (91%) and induced angiogenesis (91%). Peritumoural blood and lymphatic vessel invasion (PBLVI) by tumour emboli was observed in 6 tumours. With a median follow-up of 25 months, overall 3-year survival was 48%; disease-free survival (DFS) has not been reached yet. The only significant factor influencing DFS in multivariate analysis was PBLVI by tumour cells; PBLVI-positive patients had a significantly higher likelihood ratio (P = 0.000001) of developing metastasis than their PBLVI-negative counterparts. This study documents the prognostic implication of PBLVI by tumour cells in T4 NSCLC.

[Expression of intercellular adhesion molecule 1 (ICAM-1) on human alveolar macrophages]. / Expression de la molécule d'adhésion intercellulaire 1 (ICAM-1) sur les macrophages alvéolaires humains.

Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on alveolar macrophages (AM) may be one of the the basic mechanisms by which AM regulate the course of inflammatory response during pulmonary allograft rejection and infectious processes by mediating macrophage-lymphocyte interactions. As a model for studying anti-inflammatory activity of drugs on AM, we have investigated the effect of fusafungine, a local antibiotic which displays also anti-inflammatory properties, on the regulation of ICAM-1 membrane expression induced in vitro by stimulating AM from lung-transplant recipients. We have studied ICAM-1 membrane expression by immunocytofluorometric analysis using the anti-CD54 monoclonal antibody. The ICAM-1 molecule was expressed on 10 to 47% of freshly isolated AM, depending on the clinical status of the patients. After 24 hr cultivation with 250 U/ml gamma-IFN, the percentage of ICAM-1+ AM s increased to more than 90%. When added with the stimulating agent, fusafungine could inhibit the induction of ICAM-1 membrane expression, up to 90% of inhibition at 8 microgram/ml. However, once ICAM-1 was induced after 24 hr cultivation upon stimulation, fusafungine could not afford any reversion. On going investigations on mRNA for ICAM-1 should indicate whether fusafungine acts at the transcriptional level. These results clearly demonstrate the capacity of fusafungine to down-regulate ICAM-1 expression on AM upon activation. This approach could represent a useful tool for in vitro study of drug efficacy upon inflammatory processes of the respiratory mucasa.

Pentoxifylline and lung ischemia-reperfusion injury: application to lung transplantation. Université Paris-Sud Lung Transplant Group.

Pentoxifylline (PTX) attenuates neutrophil-mediated lung injury in several models of acute lung inflammation. Because pulmonary neutrophil sequestration is the main determinant of ischemia-reperfusion (IR) injury in lung transplantation, we sought to determine whether or not PTX prevented IR injury in isolated perfused rat and rabbit lungs submitted to IR, and in pigs after left lung allotransplantation. In rat lungs after IR, the coefficient of lung endothelial permeability (Kfc) increased by 112 +/- 12% in controls and by 27 +/- 8% (p < 0.001) in PTX-treated lungs. After IR, lung myeloperoxidase and blood neutrophil count decrease were lower with PTX than in controls, and the changes in Kfc were correlated with the percentage decrease in blood neutrophils during reperfusion. In rabbit lungs, endothelium-dependent relaxation in isolated pulmonary arterial rings was decreased in the control group and normal in the PTX group. In pigs ventilated with pure oxygen, the PaO2 was greater in the PTX group than in the control group (423 +/- 49 vs. 265 +/- 43 mm Hg; p < 0.05), whereas the total pulmonary vascular resistance was lower (15 +/- 1 vs. 30 +/- 9 mm Hg/L/min; p < 0.02). After reperfusion, the decrease in circulating leukocyte count fell by 35 +/- 3% in the control group and remained unchanged in the PTX group, and the leukocyte count per microscopic field in the transplanted lung was lower in the PTX group than in the control group (p < 0.02). In conclusion, PTX prevented IR lung endothelium injury and improved post-IR lung function by decreasing neutrophil lung sequestration, and this agent might be useful in clinical lung transplantation.

Emergence of inflammatory alveolar macrophages during rejection or infection after lung transplantation.

Local activation of macrophages may play an important role in immune complications following lung transplantation. To document such a phenomenon, we have investigated the possible changes of alveolar macrophage surface antigen expression after lung transplantation. Using immunocytofluorometry, we have analyzed the phenotype of alveolar macrophages from 41 bronchoalveolar lavage fluids obtained from 19 lung transplant recipients displaying various complications. The strong expression of HLA-DR observed on almost all alveolar macrophages was similar among groups I (no complication), II (minimal acute rejection), and III (mild to severe acute rejection), but was enhanced in group IV (bronchial infection) (P < 0.03). We observed no significant variation in the monocyte lineage CD14 antigen expression among the 4 groups, and about 83% of alveolar macrophages expressed this marker strongly. Membrane expression of the 27E10 antigen that characterizes infiltrating macrophages in acute inflammatory lesions was significantly higher during mild to severe rejection episodes than in controls (P < 0.02) and during bronchial infections (P < 0.05) but not during minimal rejection. Double staining experiments confirmed that 27E10-positive cells in groups III and IV belonged to the macrophage lineage. In addition, the expression of the 27E10 antigen on cultured alveolar macrophages was found to be increased after stimulation by bacterial lipopolysaccharide or IFN-gamma. These results indicate that a particular alveolar macrophage subpopulation is activated during immune events after lung transplantation. This population, recognized by the 27E10 mAb, might be involved in cytokine production during severe acute rejection and infection episodes.

Comparative outcome of heart-lung and lung transplantation for pulmonary hypertension.

Despite the development of several lung transplantation procedures, the most advantageous for pulmonary hypertension remains controversial. Between 1986 and February 1992, 30 patients with end-stage primary pulmonary hypertension (n = 24), chronic pulmonary embolism (n = 4), and hystiocytosis X (n = 2) underwent heart-lung (n = 21), double lung (n = 8), or single lung (n = 1) transplantation. Indications for double lung transplantation were similar to those for heart-lung transplantation, and the preoperative clinical and hemodynamic parameters were not significantly different between the two groups. There were no intraoperative deaths, but two reoperations were needed for pleural hematoma. Five early deaths were related to graft failure (two heart-lung transplantations), mediastinitis (one heart-lung transplantation), multiorgan failure (one double lung transplantation), and aspergillosis (one double lung transplantation). There was a similar improvement in early (days 0 and 2) and late (6 months postoperatively) right-sided hemodynamic function in patients undergoing heart-lung and double lung transplantation. Three double lung transplant recipients had early and reversible left ventricular-failure. The early postoperative course of the one patient who had single lung transplantation was characterized by severe pulmonary edema, left ventricular failure, and persistent desaturation and later on by moderate pulmonary hypertension and an important ventilation/perfusion mismatch. The pulmonary function results were also similar in the heart-lung and double lung transplantation groups. The overall projected 2- and 4-year survivals were 49% and 41%, respectively, and were not significantly different between the heart-lung and double lung recipients. Results demonstrate that heart-lung and double lung transplantation are equally effective in obtaining early and durable right-sided hemodynamic and respiratory improvement and similar respiratory function. In patients with pulmonary hypertension, double lung transplantation should be preferred to single lung transplantation because of the critical postoperative course and the uncertain long-term results of single lung transplantation.

[Phenotype profile of blood lymphocytes in bronchiolitis obliterans after lung transplantation]. / Profil phénotypique des lymphocytes sanguins dans la bronchiolite oblitérante après transplantation pulmonaire.

Bronchiolitis obliterans (BO) remains the major complication in long-term survivors with lung transplants, occurring in up to 30% of them. As a non-invasive follow-up of lung recipients, we studied the phenotype of peripheral blood lymphocyte subsets. Using a flow cytometric analysis, we could define a specific pattern during BO. The most important findings were 1) disappearance of the CD19+ B cell population, despite normal or increased immunoglobulin blood levels; 2) marked decrease of the CD4+/CD8+ ratio; 3) dramatic increase in phenotypic cytotoxic effector T cells CD8+S6F1+ (MHC Class I-restricted allocytotoxicity) and CD3+CD4-CD8- (MHC Class I-non restricted allocytotoxicity); 4) marked increase of the CD4+CD29+ (helper/inducer T cell) to CD4+CD45RA+ (suppressor/inducer T cell) ratio associated with the loss of phenotypic suppressor/inducer CD4+CD45RA+ T cells. Moreover, we have shown that the maintenance triple immunosuppressive regimen that consisted of cyclosporin, prednisolone and azathioprine, did not affect the relative distribution of lymphocyte subsets, except for the CD3+CD4-CD8- cytotoxic subset that was slightly decreased under therapy. Thus, using a selected combination of lymphocyte membrane antigens, sequential prospective testing should be useful in the non-invasive follow-up of lung-transplanted patients to predict and halt the progressive course towards BO.

Lack of bronchial hyperresponsiveness to methacholine and to isocapnic dry air hyperventilation in heart/lung and double-lung transplant recipients with normal lung histology. The Paris-Sud Lung Transplant Group.

To investigate whether survivors of heart/lung and double-lung transplantations have normal or increased nonspecific bronchial responsiveness, nine heart/lung and four double-lung transplant recipients with normal lung histology underwent methacholine challenge and voluntary isocapnic dry air hyperventilation (VIH) in a randomized order at a mean time of 14.8 +/- 12.1 months after surgery. Transplant recipients were compared with 10 normal subjects and 11 patients with mild asthma. Asthmatic patients had a mean provocative concentration of methacholine inducing a 20% fall (PC20) in FEV1 of 3.4 +/- 3.6 mg/ml (SD). Seventy seven percent of the transplant recipients and 70% of the normal subjects had PC20 superior to 32 mg/ml. The percentage fall from baseline FEV1 after VIH was 12.6 +/- 10.4% in asthmatic patients as compared with 1.9 +/- 2.9% in transplant recipients (p = 0.002) and 0.45 +/- 1.2% in normal subjects (p = 0.001). The decrease in FEV1 after VIH was similar in transplant recipients and normal subjects (p = 0.14). These results show that heart/lung or double-lung transplant recipients with normal lung histology have a normal response to nonspecific bronchial stimulation.

Role of CMV pneumonia in the development of obliterative bronchiolitis in heart-lung and double-lung transplant recipients.

Obliterative bronchiolitis (OB) is the main cause of late mortality after lung transplantation. Cytomegalovirus infection has been associated with late graft failure. The aim of this study was to determine whether the development of OB was related to CMV pretransplant serological status and to CMV infections. The study group comprised 36 lung transplant recipients (27 HLT and 9 DLT) who survived more than 4 months, of whom 47% developed OB (defined by the persistence of an unexplained obstructive disease: FEV1/VC < 0.7). OB occurred more frequently: (1) in seronegative recipients with seropositive donors (8/9) than in seropositive recipients (7/19) or seronegative well-matched recipients (2/8); and (2) in patients who experienced CMV pneumonia (11/16) and CMV recurrence (11/16). Since matching seronegative recipients is the best way to prevent CMV infection, we believe that seronegative grafts must be reserved for seronegative recipients.

[Heart-lung transplantation and double lung transplantation. 33 cases]. / Transplantations coeur-poumons et bipulmonaires. 33 cas.

Between June 1986 and October 1989, 29 heart lung transplantations and 4 double lung transplantations were performed at the Marie Lannelongue Hospital, Paris. The early and later course of these patients was studied. The actuarial survival rates at one and two years were 65 percent and 55 percent respectively. Bacterial infection was the main cause of early death. Late morbidity was predominantly due to cytomegalovirus infection and episodes of rejection. Respiratory function, evaluated in 19 long-term survivors, was usually normal. Only 3 patients developed a functional pattern of severe obliterative bronchiolitis probably related to uncontrolled rejections. The indications of the different types of lung transplantation are discussed: in cases of primary pulmonary hypertension or Eisenmenger's complex, heart lung transplantation is the only possible procedure. In patients with respiratory failure without cardiac dysfunction, double lung transplantation gives good functional results and makes an extra heart available for transplantation in another patient. Single lung transplantation, which gives worse functional results with a similar mortality rate, must be reserved for patients who are unable to undergo double lung transplantation.

[Bronchial tolerance to inhalation of beclomethasone. Histologic and microbiologic study in asthmatic patients]. / Tolérance bronchique à l'inhalation de béclométasone. Etude histologique et microbiologique chez l'asthmatique.

The aim of the present study was to investigate the effects of a three months' treatment with beclomethasone dipropionate on the bronchial mucosa of asthmatic patients. Eleven patients suffering from a mild chronic asthma treated with inhaled salbutamol and theophylline were randomly assigned to receive either 1000 mu g of beclomethasone dipropionate (6 patients) or an aerosolized placebo (5 patients) in a double-blind manner. Bronchial biopsies and bronchial secretions were obtained through a fiberoptic procedure at the beginning and the end of the study. Repeated clinical and spirometric investigations were performed each month. Inter- and intra-group mean changes of clinical symptoms and of spirometric values were not significantly different. Pathogens were rarely found in bronchial aspirates and their occurrence did not seem to be influenced by the beclomethasone therapy. Sixty percent of the bronchial biopsies displayed pathological changes of the mucosa that observed at the beginning and at the end of the study; however, no sign of mucosal atrophy was noted.