J. Cerrina

Pentoxifylline and lung ischemia-reperfusion injury : Application to lung transplantation

Summary 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.

Expression and modulation of ICAM-1, TNF-α 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.

Frequency of mechanical ventilation and respiratory activity after double lung transplantation

We investigated the contribution of pulmonary afferent nerve fibers to the control of inspiratory activity in awake humans. Eight double lung transplant outpatients and eight normal subjects were hyperventilated with a mechanical ventilator. Respiratory frequency was increased until no respiratory activity was detectable. Then, by either adding CO2 in the inspired gas or decreasing respiratory frequency, end-tidal PCO2 (PETCO2) was increased until inspiratory activity (i.e. change in inspiratory airway pressure peak and/or time profile) was detected. In normal subjects, PETCO2 threshold for inspiratory muscle recruitment was significantly lower when frequency was decreased than when CO2 was added (31.3 +/- 6.8 Torr vs. 38.2 +/- 8.1 Torr respectively, P < 0.005). This was not the case in the double lung transplant group (31.5 +/- 6.5 Torr vs. 32.9 +/- 5.8 Torr). These findings suggest that pulmonary afferent nerves have an inhibitory effect on inspiratory activity in humans.

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.

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.

Particular phenotypic profile of blood lymphocytes during obliterative bronchiolitis syndrome following lung transplantation.

Bronchiolitis obliterans syndrome (OBS) remains the major complication in long-term survivors with heart-lung transplants, occurring in up to 50% of patients who survived the first year postsurgery. Until now, a significant decrease in small airway flow parameters has represented the most sensitive index for the detection of early OBS. Using immunocytofluorometric analysis, in a prospective study we have analysed the phenotype of peripheral blood lymphocyte effector and regulatory subsets in seven patients with inactive well-established OBS as compared with lung transplant recipients without any complication. We found a particular phenotypic profile during well-established OBS characterized by: (1) the disappearance of the CD19+ B cell population despite normal or increased immunoglobulin blood levels; (2) a marked decrease in the CD4+/CD8+ ratio; (3) a dramatic increase in phenotypic cytotoxic effector T cells CD8+S6F1+high and CD3+CD4-CD8-; (4) a dramatic increase in the CD4+CD29+/CD4+CD45RA+ ratio associated with the loss of the phenotypic suppressor/inducer CD4+CD45RA+T cells. The results of this preliminary study suggest that, using this selected combination of lymphocyte membrane markers, sequential phenotyping could be useful in the noninvasive follow-up of lung transplant recipients. The predictive value of this phenotypic profile for the early diagnosis of OBS is under investigation.

Anesthésie et réanimation pour transplantation cœur-poumons

Resume Depuis le premier succes de Shumway en 1981, la transplantation cardiopulmonaire (TCP) represente un nouvel espoir therapeutique pour les hypertensions arterielles pulmonaires primitives ou secondaires et les insuffisances respiratoires chroniques graves. Son developpement est actuellement encore trop limite par le faible nombre de greffons disponibles. Lamelioration de la reanimation des comas depasses devrait permettre daugmenter le nombre de ces prelevements. La proscription dun remplissage vasculaire abusif en hemodilution et lutilisation de faibles doses de vasopresseurs et dhormone antidiuretique permettent de corriger lhypotension et la polyurie tout en preservant la qualite du greffon cardiopulmonaire. Les affections justiciables dune transplantation cardiopulmonaire sont caracterisees par lexistence dune hypertension arterielle pulmonaire, dune hypoxie severe et dune insuffisance cardiaque droite ou globale. Linduction anesthesique doit prevenir toute majoration de ces facteurs. La circulation extracorporelle (CEC), debutee precocement, permet une dissection dans de meilleures conditions. Apres la revascularisation du greffon, les problemes sont essentiellement dordre hemodynamique, respiratoire (œdeme pulmonaire de reimplantation) et hemorragique (saignements consecutifs a la dissection du mediastin posterieur sous CEC). Dans les suites immediates, la depletion hydrosodee est de regle, afin de limiter limportance de lœdeme pulmonaire. Elle doit cependant rester compatible avec le maintien dune hemodynamique satisfaisante. La frequence des insuffisances renales sexplique par la longueur de la CEC, lhypovolemie induite, lutilisation de produits nephrotoxiques et la frequence des complications infectieuses bacteriennes. Celles-ci (pneumopathies, mediastinites) restent la principale cause de mortalite precoce. Lamelioration des techniques chirurgicales, lextubation precoce et lintroduction tardive de la corticotherapie permettent de limiter les complications tracheales. Au-dela du 15e j postoperatoire, les complications infectieuses opportunistes et les rejets pulmonaires ou cardiaques sont au premier plan. Lexperience acquise depuis 1981 a permis dameliorer notablement les resultats de la TCP, avec des taux de survie de 70 a 80 % a un an et de 60 a 70 % a deux ans pour les meilleures equipes. Malgre la complexite de la periode initiale et la menace a long terme de levolution vers la bronchiolite obliterante, la TCP represente actuellement le seul espoir pour de jeunes patients de decouvrir ou de retrouver une vie normale.

Angiogenesis : a novel target for Adjuvant chemotherapy in locally advanced non-small cell lung cancer

Surgery remains the only curative treatment modality for non-small cell lung cancer (NSCLC). Long-term results are significantly influenced by the primary tumor (T) and lymph node (N) stages and the oncological radicality of operation. Early-staged (T 1 NOM0) tumors are highly curable by surgery alone and because of its cost-benefit ratio, adjuvant therapy is not recommended [1]. For more advanced disease (any T3–4, N 1–2M0), operation still represents the only chance for cure but long-term results are largely influenced by the biological operability and dependent from the T and N subset categories [2] .

Extented resection after primary chemotherapy for residual malignant non-seminomatous germ-cell tumors of the mediastinum : is it worthwhile?

Primary malignant non-seminomatous germ cell tumours are rare neoplasms accounting for only 1 to 3.5 % of all mediastinal malignancies and 1 to 2 % of all germ cell tumours in male patients [1]. Although they share many histological and serological features [2], their clinical and biological behaviour is different from their testicular counterparts [3, 4]. Most of them present as bulky anterior mediastinal masses that frequently involve surrounding structures or organs, lack of radiosensitivity, are rarely cured by surgical resection alone and have a poor prognosis [5].