Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-kappaB and endothelin-1.

Pulmonary hypertension is rare in chronic respiratory diseases but has a strong impact on the prognosis and is partly underlined by factors other than hypoxaemia. The aim of the present study was to assess the potential role of endothelin-1 (ET-1) and nuclear factor (NF)-kappaB vasoconstrictive pathways in pulmonary hypertension. The effects of ET-1 receptors blockers (BQ 123 and 788) and of genistein were assessed on response to acetylcholine of pulmonary vascular rings from cystic fibrosis (CF) lung transplant recipients (n = 23). NF-kappaB and ET-1 receptor expression was immunodetected in pulmonary arteries and quantitated using Western blotting. ET-1 vascular content was quantitated using ELISA. In total, 14 out of 23 subjects exhibited strongly impaired pulmonary vasodilation (p<0.01 versus nine out of 23 subjects with a normal response) associated with an activation of ET-1 receptors A and NF-kappaB pathways. Genistein restored vasodilation in subjects with an abnormal response. Pulmonary vascular dysfunction is frequent in end-stage CF, involving the NF-kappaB pathway and that of ET-1 through ET-1 receptor A (ETAR). These data leave a conceptual place for ETAR blockers and isoflavones in the management of the devastating vascular complication of chronic obstructive respiratory diseases such as CF.

[Evolution and progress of lung transplantation: An analysis of a cohort of 600 lung transplant patients at the Hospital Foch]. / Évolution et progrès en transplantation pulmonaire : étude de la cohorte de 600 premiers patients transplantés pulmonaires à l'hôpital Foch.

Lung transplantation is deemed to be the only effective therapy that improves survival for patients with end stage lung disease. The aim of our study was to examine the progress achieved over the last two decades and to demonstrate the effectiveness and safety of this treatment. METHODS: A retrospective analysis of a cohort of 600 consecutive lung transplant patients treated at the hospital Foch (Suresnes, France) between 1988 and 2014. They were split into three groups of 200 patients each: 1988-2004, 2004-2011, 2011-2014. RESULTS: Time and mortality on waiting list, perioperative mortality, the incidence of acute rejection in the first year and chronic lung allograft dysfunction (CLAD) at 5 years posttransplantation, have all decreased. Global survival at 1 and 5 years for the 600 patients increased from 78% and 57% to 86% and 75% respectively for the 200 last patients. Patients with cystic fibrosis have a better 5 year survival than those with emphysema or pulmonary fibrosis (68% vs. 54 % for emphysema and 37% for fibrosis). For the last 200 patients, 5 year survival is 81% for CF patients, 78 % for emphysema and 47% for fibrosis. Emergency transplantation had a 60% 5 years survival. Proliferative complications, arterial hypertension and renal function impairment are being monitored long term. CONCLUSION: The twenty-five years experience shows a consistent improvement in the results of lung transplantation which is now accepted as the only effective curative treatment for end stage lung disease.

Clinical outcome following lung transplantation in patients with cystic fibrosis colonised with Burkholderia cepacia complex: results from two French centres.

BACKGROUND: Infection with Burkholderia cepacia complex (BCC) is a life threatening complication of cystic fibrosis (CF), often seen as a contraindication for lung transplantation. METHODS: A long term retrospective study was conducted of all patients with CF undergoing lung transplants from January 1990 to October 2006 in two French centres allowing transplantation in patients colonised with BCC. RESULTS: 22 of the 247 lung transplant patients with CF were infected with BCC (B. cenocepacia genomovar III (n = 8), B. multivorans genomovar II (n = 11), B. vietnamiensis genomovar V (n = 2) and B. stabilis genomovar IV (n = 1)). BCC colonisation was not associated with any significant excess mortality (HR 1.5, 95% CI 0.7 to 3.2; p = 0.58). However, early mortality rates tended to be higher in the BCC group than in the non-BCC group (3 month survival: 85% vs 95%, respectively; log rank p = 0.05). Univariate analysis showed that the risk of death was significantly higher for the eight patients infected with B. cenocepacia than for the other 14 colonised patients (HR 3.2, 95% CI 1.1 to 5.9; p = 0.04). None of the other risk factors tested-primary graft failure, late extubation, septicaemia-had a significant effect. The 5 year cumulative incidence rate of bronchiolitis obliterans syndrome was not significantly higher in the BCC group than in the non-BCC group (38% vs 24%, respectively; p = 0.35). CONCLUSION: Our results suggest that BCC infection with a non-genomovar III organism may not be associated with excess mortality after lung transplantation in patients with CF and should not be seen as sufficient reason to exclude lung transplantation. However, colonisation with B. cenocepacia remains potentially detrimental.

Mutations of the Drosophila dDP, dE2F, and cyclin E genes reveal distinct roles for the E2F-DP transcription factor and cyclin E during the G1-S transition.

Activation of heterodimeric E2F-DP transcription factors can drive the G1-S transition. Mutation of the Drosophila melanogaster dE2F gene eliminates transcriptional activation of several replication factors at the G1-S transition and compromises DNA replication. Here we describe a mutation in the Drosophila dDP gene. As expected for a defect in the dE2F partner, this mutation blocks G1-S transcription of DmRNR2 and cyclin E as previously described for mutations of dE2F. Mutation of dDP also causes an incomplete block of DNA replication. When S phase is compromised by reducing the activity of dE2F-dDP by either a dE2F or dDP mutation, the first phenotype detected is a reduction in the intensity of BrdU incorporation and a prolongation of the labeling. Notably, in many cells, there was no detected delay in entry into this compromised S phase. In contrast, when cyclin E function was reduced by a hypomorphic allele combination, BrdU incorporation was robust but the timing of S-phase entry was delayed. We suggest that dE2F-dDP contributes to the expression of two classes of gene products: replication factors, whose abundance has a graded effect on replication, and cyclin E, which triggers an all-or-nothing transition from G1 to S phase.

[Radical surgery for mesothelioma]. / La chirurgie radicale dans le mésothéliome.

Good results obtained by the team from Boston increased the interest in pleuropneumonectomy for mesothelioma. Adjuvant high-dose hemithoracic radiation after surgical resection decreased the local recurrence rate from 35 to 13%. The high rate of peritoneal (26-31%), controlateral pleural and pericardial recurrences justify the routine practice of preoperative laparoscopy and controlateral thoracoscopy and a pleuropneumonectomy without pericardotomy and diaphragmatic resection. The diaphragm is lowered to facilitate radiotherapy. Chemotherapy may be performed postoperatively.

[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.

[What place for lung volume reduction surgery for emphysema?] / Quelle place pour la réduction de volume pulmonaire chirurgicale dans l'emphysème ?

Lung volume reduction surgery (LVRS) has been part of the management for the treatment of selected emphysematous patients for two decades. In a large randomized American trial (NETT), lung volume reduction surgery was shown to improve overall survival at 5 years as well as exercise capacity and health-related quality of life, especially in cases of upper-lobe-predominant emphysema and low exercise capacity. Inclusion criteria were pretreatment FEV1≤45 %, TLC≥100 %, RV≥150 %, room air resting PaCO2≤60mmHg and PaO2≥45mmHg. Patients with FEV1≤20 % and either a DLCO<20 % or homogeneous emphysema were at increased risk of mortality following LVRS and should not be considered for this procedure. Despite this evidence base, lung volume reduction surgery is performed infrequently, competing with lung transplantation and new endoscopic volume reduction techniques.

[Lymph node clearance]. / Le curage ganglionnaire.

The goal of mediastinal sampling or a radical lymph node resection after lung cancer resection is to correctly stage the illness to enable a more accurate assessment of prognosis. Metastasis to mediastinal nodes may be encountered even in small peripheral T1 tumours. Radical lymph node resection often uncovers metastases that would have been missed by mediastinal sampling alone. The morbidity associated with radical node resection is very low, and long term survival appears to be improved, compared with node sampling. At present, lymph node staging has little influence on the choice of adjuvant treatments.

A new technique for double lung transplantation. "Bilateral single lung" transplantation.

Two techniques are currently practiced to achieve bilateral lung transplantation for the treatment of patients with end-stage pulmonary disease associated with infection: heart-lung transplantation, which is illogical, and double lung transplantation by the Toronto technique, which is difficult and entails tracheal complications. After our short experience with single lung transplantation without any bronchial problems, we have performed three double lung transplantations by a new technique, "bilateral single lung" transplantation. After a sternal bithoracotomy, first one lung was transplanted and then the other, without cardiopulmonary bypass. This bilateral single lung transplantation provides all the advantages of single lung transplantation and is particularly recommended for use in patients with severe pleural adhesions.

Single lung transplantation for pulmonary lymphangiomyomatosis. Unexpected need for extracorporeal circulation.

The present case describes an acute respiratory-related hemodynamic failure during a single left lung transplantation in a 32-year-old woman suffering from end-stage pulmonary lymphangiomyomatosis. During the first 5 min of single right lung ventilation, a progressive increase in airway pressure and decrease in tidal volume associated with a decrease in arterial pressure and Spo2 occurred that were successfully countered by reventilation of the left lung. Proper positioning of the double-lumen tube was confirmed with a fiberoptic bronchoscope. Despite deliberate hypoventilation, within a few respiratory cycles, each further attempt at single lung ventilation was followed by abrupt hypotension, increase in pulmonary artery pressure, while airway pressure rose and tidal volume collapsed. The surgical team saw no signs of right pneumothorax. In these circumstances, cardiopulmonary bypass was required to perform pneumonectomy and grafting. Postoperatively a right anterior pneumothorax remained undiscovered on standard radiograph but was later revealed on soft radiograph. This acute intraoperative respiratory failure could equally well have been related to air trapping, in which case, however, deliberate hypoventilation would have been effective. In addition, the striking difference between the progressive onset of the first episode of hemodynamic failure and the immediate onset of the others argues in favor of a pneumothorax being at cause. Patients with pulmonary lymphangiomyomatosis are at high risk for intraoperative pneumothorax, but in our case, it could not be confirmed and treated during the surgical procedure without putting the patient at high risk for lung injury because of pleurodesis due to earlier pleural abrasion. This case again clearly shows the need to have cardiopulmonary bypass whenever single lung transplantation is performed.

Surgical management of non-small cell lung cancer with synchronous brain metastases.

OBJECTIVES: Published series on the synchronous combined resection of brain metastases and primary non-small cell lung cancer are small and scarce. We therefore undertook a multicenter retrospective study to determine long-term survival and identify potential prognostic factors. DESIGN: Our series includes 103 patients who were operated on between 1985 and 1998 for the following tumors: adenocarcinomas (74); squamous cell carcinomas (20); and large cell carcinomas (9). Three patients had two brain metastases, and one patient had three metastases; the remaining patients had a single metastasis. Ninety-three patients presented with neurologic signs that regressed completely after resection in 60 patients and partially, in 26 patients. Neurosurgical resection was incomplete in six patients. Seventy-five patients received postoperative brain radiotherapy. The time interval between the brain operation and the lung resection was < 4 months. Pulmonary resection was incomplete in eight patients. RESULTS: The survival calculated from the date of the first operation was 56% at 1 year, 28% at 2 years, and 11% at 5 years. Univariate analysis showed a better prognosis for adenocarcinomas (p = 0.019) and a trend toward a better prognosis for patients with small pulmonary tumors (T1 vs T3, p = 0.068), N0 stage disease (N0 vs N+, p = 0.069), and complete pulmonary resection (p = 0.057). In a multivariate analysis, adenocarcinoma histology also affected the survival rate (p = 0.03). CONCLUSIONS: It seems legitimate to proceed with lung resection after complete resection of a single brain metastasis, at least in patients with an adenocarcinoma and a small lung tumor and without abnormal mediastinal lymph nodes seen on the CT scan or during mediastinoscopy.

Tracheal sleeve resection for iatrogenic stenoses (subglottic laryngeal and tracheal).

Since 1975 200 tracheal sleeve resections for iatrogenic tracheal and subglottic laryngeal stenoses have been performed in our institution. Preoperative Nd:YAG laser is of paramount help in opening the stenoses. Tracheography is usually performed to specify the length of the stenosis and the distance from the vocal cords. Operative procedures are described. One hundred seventy five (87.5%) patients are definitely cured, but in this group 16 patients required a Montgomery tube for 6 months to 1 year to recover a normal tracheal diameter. Two patients needed a second tracheal sleeve resection. Nine (4.5%) patients died, and 16 (8%) had recurrent stenoses. Stenoses in these patients were treated with use of a tracheostomy tube, a permanent Montgomery tube, or an endotracheal stent. Partial anterior cricoid resections performed in 21 patients have had the same results as those of the whole series. Twenty one laryngeal releases were performed and proved to be efficient and safe. In our experience complications can be avoided by good selection and preparation of the patients, accurate identification of the level and length of the stenosis, and meticulous technique.

Bilateral pulmonary lobe transplantation: left lower and right middle and lower lobes.

It is difficult to find lungs of appropriate size for double-lung transplantation in teenagers and small adults. Nevertheless, many young patients suffering from cystic fibrosis are waiting for lung transplantation. We have performed two bilateral lobar transplantations (left lower lobe plus right middle and lower lobe) with good recovery. Details of the technique are described.

Left lower lobe transplantation during a bilateral single lung transplantation (pulmonary lobe transplantation).

An isolated left lower lobe was used as a left graft, during a bilateral single lung transplantation procedure, in a patient with infected fibrosis. This technique is suitable for patients with small lung volume (especially cystic fibrosis) or asymmetric retraction.

Bilateral single lung transplantation. Complications and results in 14 patients.

Between November 1989 and April 1991, 14 bilateral single lung transplantations (BSLT) were performed at our institution using the technique we have described without omentoplasty and rarely cardiopulmonary bypass. The indications included emphysema (8), cystic fibrosis (3), infected fibrosis (1), alveolar microlithiasis (1) and lymphocytic interstitial pneumonitis (1). Maximum mean pulmonary artery pressure was 53 mmHg and minimal right ventricular ejection fraction was 15%. Two patients experienced bronchial complications: 1 complete left bronchial dehiscence, 1 late partial stenosis which required a temporary insertion of a stent. One patient had a posterior dehiscence which healed spontaneously. Five patients died postoperatively (3 of infection, 1 after a volume mismatch and 1 after a circulating anticoagulant). BSLT is the technique of choice for double lung transplantation in adults and heart lung transplantation has very few indications in infected end-stage pulmonary disease. We hope that modification of our immunosuppressive regimen will decrease postoperative mortality.

[Surgical morbidity for bronchial cancers after neoadjuvant treatment]. / Morbidité de la chirurgie des cancers bronchiques après traitement néoadjuvant.

Two randomized trials, in 1994, have demonstrated the benefit of neoadjuvant chemotherapy, in term of median survival, for stage III lung cancer. Further studies have evaluated the potential benefit of chemotherapy or chemotherapy-radiotherapy association, either for patients suitable for surgery, or for non resectables tumors. However, these treatments treatments may increase the morbidity of surgery. Such an increase has not been demonstrated, except in one study, after chemotherapy alone before surgery. When radiation therapy is associated with pre-operative chemotherapy, the risk of complications seems to be dose dependent: low for doses below 50 Gy, important for doses over 55 Gy. These datas justify pre-operative lung function measurements and modifications of the surgical technic, especially for the lymphadenectomy extension. Despite this potential increase of morbidity, the benefit of neoadjuvant treatment is real.

[Gross tumor volume and clinical target volume in radiotherapy: lung cancer]. / Volume tumoral macroscopique et volume-cible anatomoclinique en radiothérapie: cancer bronchique.

Radiotherapy plays a major role as a curative treatment of various stages non-small cell lung cancers (NSCLC): as an exclusive treatment in curative attempt for patients with unresectable stages I and II; as a preoperative treatment, which is often associated with chemotherapy, for patients with surgically stage IIIA NSCLC in clinical trials; in association with chemotherapy for unresectable stages IIIA and IIIB patients. Currently, three-dimensional conformal radiotherapy allows for some dose escalation, increasing radiation quality. However, the high inherent conformality of this radiotherapy technique requires a rigorous approach and an optimal quality of the preparation throughout the treatment procedure and specifically of the accurate definition of the safety margins (GTV, CTV...). Different questions remain specific to lung cancers: 1) Despite the absence of randomized trials, the irradiated lymph nodes volume should be only, for the majority of the authors, the visible macroscopically involved lymph nodal regions. However, local control remains low and solid arguments suggest the poor local control is due to an insufficient delivered dose. Therefore the goal of radiotherapy, in this particular location, is to improve local control by increasing the dose until the maximum normal tissue tolerance is achieved, which essentially depends on the dose to the organs at risk (OAR) and specifically for the lung, the esophagus and the spinal cord. For this reason, the irradiated volume should be as tiny as possible, leading to not including the macroscopically uninvolved lymph nodes regions in prophylactic view in the target volume; 2) The lung is one of the rare organs with extensive motion within the body, making lung tumors difficult to treat. This particular point is not specifically considered in the GTV and CTV definitions but it is important enough to be noted; 3) When radiation therapy starts after a good response to chemotherapy, the residual tumoral volume should be defined as the target volume in place of the initial tumor volume. These different elements are discussed in this paper.

[Lung transplantation]. / Transplantation pulmonaire.

Lung transplantation began to expand in 1983, after the advent of cyclosporin and the publication of the Toronto lung transplant group study. Single lung transplantation was first performed in patients with interstitial pneumopathy to be extended later to pulmonary emphysema, then to primary or secondary pulmonary arterial hypertension. Double lung transplantation provides patients suffering from chronic lung infection (e.g. cystic fibrosis) with a useful alternative to their ordinary treatment. The experience acquired throughout these years has resulted in wider criteria for patients' inclusion. More than acute rejection, bacterial infections directly condition the immediate prognosis. The frequency and severity of cytomegalovirus lung diseases lead to a discussion on the possibility of prophylactic and curative antiviral therapy. The occurrence of obliterative broncholitis, which reflects chronic lung rejection, jeopardizes the long-term results of transplantation. The functional results of the various types of lung grafting are analysed, and the position of lung transplantation in thoracic surgery is reassessed.

[A new technique for double lung transplantation. "The bilateral single lung transplantation". Apropos of ten operations]. / Une nouvelle technique de greffe bipulmonaire. "La double unilatérale". A propos de dix interventions.

The technique of enbloc double lung transplantation described by the Toronto team, with cardiopulmonary bypass, cardioplegia, and tracheal suture is complicated by problems of tracheal anastomosis for its authors. Single lung transplantation has a more straight forward postoperative course and bronchial complications are moderate. We present a new technique of lung transplantation, the "bilateral single lung transplantation". It consists, via a single anterior horizontal incision, of successively performing two single lung transplantations without bypass. This operation has been performed ten times since November 1989. As expected, bronchial healing has been excellent.

[Donor-recipient lung volume matching in double lung transplantation. Value of left lower lobe graft]. / Adéquation volumétrique donneur-receveur en greffe bipulmonaire. Intérêt de la greffe lobaire inférieure gauche.

For double lung transplantation, lung volume matching is easier comparing the predicted total lung capacities of the donor and recipient and the recipient's true TLC. The major concern in the inability to close the chest when the donor lungs are too large. The technique reported of left lower lobe implantation during bilateral single lung transplantation might be of great value in patients with small lung volume.