Results of Lung Transplantation for Cystic Fibrosis With Selected Donors Over 65 Years Old.

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

A Horseshoe Intralobar Lung Sequestration Resection by Bilateral Robot-Assisted Surgery.

We present the case of a 20-year-old male patient presenting a right lower intralobar pulmonary "horseshoe" sequestration extending into the left cavity supplied by 4 aberrant arteries from the thoracic descending aorta. The surgical approach for this exceptional and challenging presentation was based on thorough analysis of the chest computed tomography scan aided by 3-dimensional reconstructions. The latter helped us better understand this complex malformation. Surgery was done by robot-assisted bilateral approach with en bloc extraction through the left side.

High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.

Significant rational is available for specific targeting of PI3K/AKT/mTOR pathway in the treatment of non-small cell lung cancer (NSCLC). However, almost all clinical trials that have evaluated Pi3K pathway-based monotherapies/combinations did not observe an improvement of patient's outcome. The aim of our study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus. An in vivo study showed high efficacy of RAD001 in NSCLC Patient-Derived Xenografts (PDXs). When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., PLK1, CXCR4, and AXL. We have then focused our study on the combination of RAD001 + Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an in vitro study. Pharmacodynamics study demonstrated that this synergy was due to (1) tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and (2) decrease of the Carbonic Anhydrase 9 (CAIX) protein that could not correct intracellular acidosis. In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients.

Optimal Management With Radical Resection of Obstructive Primary Chondrosarcoma of the Trachea.

We report 2 cases of chondrosarcoma of the trachea. This etiology of tracheal tumors is exceptional, and only a few cases have been reported so far. The optimal management for these 2 cases was challenging. First an interventional bronchoscopy was required for biopsy and to prevent airway obstruction. Second a radical en bloc resection with free margins was performed through a sternotomy in the first case and by a cervicotomy in the second case. Fifty and 6 months after surgery the 2 patients are alive with no local or distant recurrence.

The role of three-dimensional reconstructions in understanding the intersegmental plane: an anatomical study of segment 6.

OBJECTIVES: The identification of the intersegmental plane during lung segmentectomies remains a practical difficulty, notably with minimally invasive approaches. The intraoperative techniques are based on demarcating either the bronchial or the vascular territories. The goal of this study was to evaluate the use of 3-dimensional reconstructions in understanding the intersegmental plane of segment 6. METHODS: Between March and September 2018, Synapse 3-dimensional programme was used to carry out bilateral venous, arterial and bronchial segmentations of segment 6. All computed tomography (CT) scans were contrast-enhanced and of a high resolution (0.6 mm slices). The patients had normal results on respiratory function tests. The volumes obtained from each of the 3 modalities were then compared. The results are presented as mean and standard deviation and as median and interquartile ranges for lung volume measurements. RESULTS: During the aforementioned period, 15 high-resolution chest CT scans were selected (8 men and 7 women). The median age was 70 years. In all of the studied segments (N = 30, 15 right S6 and 15 left S6), the segmental volume of the vein was greater than the segmental volumes of the bronchus and the artery. A significant difference was found between the segmental volumes obtained from the 3 modalities (P = 0.001). The segmental volume of the vein was significantly higher than the segmental volume of the bronchus (P < 0.001) and the segmental volume of the artery (P < 0.001). On the other hand, the segmental volume of the artery was significantly higher than the segmental volume of the bronchus (P = 0.01). CONCLUSIONS: Within the limits of this study, the segmental venous volume of S6 was greater than the volumes of the segmental bronchial and arterial volumes. Thus, depending solely on bronchial techniques might lead to leaving a border zone in venous congestion.

Hanging donor lungs give good short-, mid- and long-term results in lung transplantation.

BACKGROUND: Hanging donors are considered as marginal donors and frequently unsuitable for lung transplantation. However, there is no evidence of higher lung transplantation (LTx) morbidity-mortality with lungs providing by hanging donor. METHODS: Between January 2010 and July 2015, we performed a retrospective study at Foch hospital. We aimed to assess whether hanging donor grafts are suitable for lung transplantation. RESULTS: A total of 299 LTx were performed. Subjects were allocated to a hanging group (HG) (n = 20) and a control group (CG) (n = 279). Donor and recipient characteristics did not differ. Primary graft dysfunction (PGD) at 72 hours was comparable in both groups (P = .75). The median duration of postoperative mechanical ventilation (1 [range, 0-84] vs 1 [range, 0-410] day, P = .35), the hospital length of stay (31 days [20-84] vs 32 days [12-435], P = .36) did not differ between the two groups. No statistically significant difference was found in 1-year and 5-year survival between the HG (83% and 78%) and the CG (86% and 75%), P = .85. CONCLUSION: We believe that hanging donors should be considered as conventional donors with particular caution in the final evaluation of the graft and in perioperative management.

Use of 3-dimensional computed tomography for planning a complex sleeve bronchoplasty with total parenchyma-sparing resection of a carcinoid tumour in the right main bronchus.

Bronchoplasty is frequently required for radical resection of central typical carcinoid tumours. As sleeve bronchoplasty can be a complex procedure, an accurate evaluation of the tumour location is mandatory. Although the endobronchial part of the tumour can be easily evaluated by bronchoscopy, the exo-bronchial part is difficult to analyse with a standard computed tomography (CT) scan. A three-dimensional (3D) CT scan could be used to identify this exo-bronchial component of the tumour when planning a reconstruction. Herein, we present a case of a 59-year-old woman with a typical central carcinoid tumour of the right main bronchus. After 3D modelling, we successfully performed a total parenchyma-sparing resection with an intermedius bronchus reimplantation into the carina associated with the right upper bronchus anastomosis in the lateral trachea. The follow-up was uneventful. An endoscopy at 3 months showed excellent results.

Extracorporeal membrane oxygenation for grade 3 primary graft dysfunction after lung transplantation: Long-term outcomes.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is an efficient and innovative therapeutic tool for primary graft dysfunction (PGD). However, its effect on survival and long-term lung function is not well known. This study evaluated those parameters in patients with PGD requiring ECMO. METHOD: This single-center, retrospective study included patients who underwent LTx at our institute between January 2007 and December 2013. Patients and disease characteristics, survival, and pulmonary function tests were recorded. RESULTS: A total of 309 patients underwent LTx during the study period and 211 were included. The patients were predominantly male (53.5%), the median age was 39 years, and the primary pathology was suppurative disease (53.1%). ECMO for PGD was mandatory in 24 (11.7%) cases. Mortality at 3 months in the ECMO group was 50% (N = 12). However, long-term survival after PGD did not correlate with ECMO. Forced expiratory volume and vital capacity were significantly reduced in patients with PGD requiring ECMO, especially those with idiopathic pulmonary fibrosis. CONCLUSION: Veno-arterial ECMO appears to be suitable for management of PGD after LTx. Patients with PGD requiring ECMO show increased initial mortality; however, long-term survival was comparable with that of other patients in the study. Lung function does not appear to be related to PGD requiring ECMO.

Natural History of Localized and Locally Advanced Atypical Lung Carcinoids after Complete Resection: A Joined French-Italian Retrospective Multicenter Study.

BACKGROUND: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. METHODS: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. RESULTS: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000-0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. CONCLUSIONS: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced.

Exhaustive preoperative staging increases survival in resected adrenal oligometastatic non-small-cell lung cancer: a multicentre study.

OBJECTIVES: Adrenal oligometastatic non-small-cell lung cancer is rare, and surgical management remains controversial. METHODS: We performed a multicentre, retrospective study from January 2004 to December 2014. The main objective was to evaluate survival in patients who had undergone adrenalectomy after resection of primary lung cancer. Secondary objectives were to determine prognostic, survival and recurrence factors. RESULTS: Fifty-nine patients were included. Forty-six patients (78%) were men. The median age was 58 years [39-75 years]. Twenty-six cases (44%) showed synchronous presentation, and 33 cases (56%) had a metachronous presentation. The median time to onset of metastasis was 18.3 months [6-105 months]. The 5-year overall survival rate was 59%; the median survival time was 77 months [0.6-123 months]. A recurrence was observed in 70% of the population. Mediastinal lymph node invasion (P = 0.035) is a detrimental prognostic factor of survival. CONCLUSIONS: After exhaustive staging, patients with adrenal oligometastatic non-small-cell lung cancer benefit from bifocal surgery.

Lung cancer in renal transplant recipients: A case-control study.

INTRODUCTION: Solid organ transplant patients are at heightened risk of several cancers compared to the general population. Secondary to a higher number of procedures and better survival after transplantation, cancer is a rising health concern in this situation. Limited data exist for lung cancer (LC) after renal transplantation. We report here the most important series of renal transplant recipients with lung cancer. METHODS: Retrospective study of all cases of LC diagnosed in three French Renal Transplant Units from 2003 to 2012. A control group consisted of non-transplant patients with LC matched with the cases for age (<30; 30-50; 50-65; >65 years), gender and diagnosis date. We recruited two controls for each case. RESULTS: Thirty patients (median age 60 years; range 29-85; male/female ratio 80/20%) with LC were analysed. LC incidence was 1.89/1000 person-years over the period 2008-2012. All patients were former or active smokers (median 30 pack-years). Transplanted patients had significantly more comorbidities, mainly cardiovascular disease. The median interval of time from kidney transplantation (KT) to diagnosis of LC was 7 years (range 0.5-47 years). LC was incidentally diagnosed in 40%. Most patients (70%) had advanced LC (stage III or IV) disease. Stage of LC at diagnosis was similar in cases and controls. Surgery and chemotherapy were proposed to the same proportion of patients. In cases, mortality was cancer related in 87% and median survival time after diagnosis was 24 months. Survival was not significantly different between the 2 groups. CONCLUSION: Despite frequent medical and radiological examinations, diagnosis of LC is usually made at an advanced stage and the overall prognosis remains poor.

Real-Time Computed Tomography Highlights Pulmonary Parenchymal Evolution During Ex Vivo Lung Reconditioning.

Ex vivo lung perfusion (EVLP) has been developed as a method to reassess and recondition marginal lungs. However, evaluation during procedures is limited to a combination of physiologic variables such as gas exchange, pulmonary mechanics, and pulmonary vascular resistance. The aim of this study was to analyze the feasibility of real-time computed tomographic (CT) imaging to improve the evaluation of the lung during EVLP procedures.

Logistic ex Vivo Lung Perfusion for Hyperimmunized Patients.

Hyperimmunized patients have restricted access to lung transplantation because of the low rate of donor lung availability. Sensitization to human leukocyte antigen is associated with acute rejection, allograft dysfunction, and decreased survival. Prospective crossmatching could allow matching a lung graft with the recipient; however, such a strategy would increase graft ischemia, with a worse impact on the long-term results of lung transplantation. We used logistic ex vivo lung perfusion for 3 patients at the Foch Hospital while waiting for a negative result of the prospective crossmatching and then moved forward to lung transplantation. All patients are alive 3 years after bilateral lung transplantation.

Radical Carinal Resection for a Glomic Tumor.

We report the case of a 33-year-old woman who presented with increasing dyspnea secondary to a tumor arising from the carina. After desobstruction by bronchoscopy, the pathologic analysis revealed a glomic tumor. Carinal resection and reconstruction were performed with venoarterial extracorporeal membrane oxygenation support. The patient's postoperative course was uneventful, and the long-term result was excellent.

Feasibility and results of a fast-track protocol in thoracic surgery.

BACKGROUND: A rehabilitation program, a multimodal strategy favoring rapid postoperative return to autonomy, has rarely been undertaken after thoracic surgery compared to colectomy. The primary outcome of this fast-track program was the length of postoperative stay. Secondary outcomes concerned the feasibility of this strategy, the incidence of postoperative complications and 3-month postoperative mortality. METHODS: Patients were included in this prospective single-center observational study if they were scheduled for lung resection (lobectomy or wedge resection) performed by posterolateral thoracotomy. The rehabilitation program, coordinated by a referent nurse, included a list of actions to be done, especially early feeding and ambulation, multimodal analgesia including epidural analgesia, early removal of chest tube. RESULTS: One hundred and two patients were included in total with two exclusions (failure of epidural analgesia). The postoperative hospital stay was 8 (7-10) days (median [25-75th percentiles]); this duration was similar to that of the historical cohort which was 9 [7-13] days (P=0.06). Most actions were conducted with a high level of acceptance except for the insertion of a single chest tube (19%) and its removal later than expected in the program. Only 50% of patients left hospital shortly after exit criteria were met suggesting failure in the organization. Patients' satisfaction rate reached 77% and no postoperative death was reported during the follow-up period. CONCLUSION: A program for early rehabilitation is feasible after thoracotomy. Chest drainage and organization to optimize the length of stay are crucial points.

Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans.

CD4(+) regulatory T (Treg) cells expressing CD25 and the transcription factor forkhead box P3 (FOXP3) are indispensable for immunological self-tolerance and homeostasis. FOXP3(+)CD25(+)CD4(+) T cells in humans, however, are heterogeneous in function and differentiation status, including suppressive or nonsuppressive cells as well as resting or activated Treg cells. We have searched for cell surface markers specific for suppression-competent Treg cells by using a panel of currently available monoclonal antibodies reactive with human T cells. We found that CD15s (sialyl Lewis x) was highly specific for activated, terminally differentiated, and most suppressive FOXP3(high) effector Treg (eTreg) cells and able to differentiate them in various clinical settings from nonsuppressive FOXP3(+) T cells secreting inflammatory cytokines. For example, CD15s(+)FOXP3(+) eTreg cells were increased in sarcoidosis, whereas it was nonsuppressive CD15s(-)FOXP3(+) T cells that were expanded in lupus flares. FOXP3(+) cells induced from conventional CD4(+) T cells by T-cell receptor stimulation hardly expressed CD15s. CD15s(+)CD4(+) T-cell depletion was sufficient to evoke and enhance in vitro immune responses against tumor or viral antigens. Collectively, we have identified CD15s as a biomarker instrumental in both phenotypic and functional analysis of FOXP3(+)CD4(+) T-cell subpopulations in health and disease. It allows specific targeting of eTreg cells, rather than whole FOXP3(+)CD4(+) T cells, in controlling immune responses.

High Emergency Lung Transplantation: dramatic decrease of waiting list death rate without relevant higher post-transplant mortality.

Many candidates for lung transplantation (LT) die on the waiting list, raising the question of graft availability and strategy for organ allocation. We report the experience of the new organ allocation program, "High Emergency Lung Transplantation" (HELT), since its implementation in our center in 2007. Retrospective analysis of 201 lung transplant patients, of whom 37 received HELT from 1st July 2007 to 31th May 2012. HELT candidates had a higher impairment grade on respiratory status and higher Lung Allocation Score (LAS). HELT patients had increased incidence of perioperative complications (e.g., perioperative bleeding) and extracorporeal circulatory assistance (75% vs. 36.6%, P = 0.0005). No significant difference was observed between HELT and non-HELT patients in mechanical ventilation duration (15.5 days vs. 11 days, P = 0.27), intensive care unit length of stay (15 days vs. 10 days, P = 0.22) or survival rate at 12 (81% vs. 80%), and 24 months post-LT (72.9% vs. 75.0%). Lastly, mortality on the waiting list was spectacularly reduced from 19% to 2% when compared to the non-HELT 2004-2007 group. Despite a more severe clinical status of patients on the waiting list, HELT provided similar results to conventional LT. These results were associated with a dramatic reduction in the mortality rate of patients on the waiting list.

Natural killer cell deficiency in patients with non-Hodgkin lymphoma after lung transplantation.

BACKGROUND: Post-transplant non-Hodgkin lymphoma (NHL) is a well-recognized complication of solid-organ transplantation, and pharmacologic suppression of adaptive immunity plays a major role in its development. However, the role of natural killer (NK) cells in post-lung transplant de novo NHL is unknown. METHODS: Extensive phenotypic analyses of NK cells from patients diagnosed with NHL after liver or lung transplantation were conducted with multicolor flow cytometry. Polyfunctionality assays simultaneously assessed NK cell degranulation (CD107a) and intracellular cytokine production (interferon-γ and tumor necrosis factor-α) in the presence of NHL target cells. RESULTS: The development of de novo NHL is linked to NK-cell maturation defects, including overexpression of NKG2A and CD62L and down-modulation of inhibitory killer immunoglobulin-like receptors and CD57 receptors. More importantly, in patients who developed NHL after lung transplantation, we observed a specific down-modulation of the activating receptors (NKp30, NKp46, and NKG2D) and a sharp decrease in perforin expression and degranulation against NHL target cells. CONCLUSIONS: Our results suggest that accumulation of abnormal NK cells could play a role in the outgrowth of NHL after lung transplantation, independently of the immunosuppressive regimen.

Wnt/ß-catenin signaling modulates human airway sensitization induced by ß2-adrenoceptor stimulation.

BACKGROUND: Regular use of ß2-agonists may enhance non-specific airway responsiveness. The wingless/integrated (Wnt) signaling pathways are responsible for several cellular processes, including airway inflammation and remodeling while cAMP-PKA cascade can activate the Wnt signaling. We aimed to investigate whether the Wnt signaling pathways are involved in the bronchial hyperresponsiveness induced by prolonged exposure to ß2-adrenoceptor agonists in human isolated airways. METHODS: Bronchi were surgically removed from 44 thoracic surgery patients. After preparation, bronchial rings and primary cultures of bronchial epithelial cells were incubated with fenoterol (0.1 µM, 15 hours, 37 °C), a ß2-agonist with high intrinsic efficacy. The effects of inhibitors/blockers of Wnt signaling on the fenoterol-induced airway sensitization were examined and the impact of fenoterol exposure on the mRNA expression of genes interacting with Wnt signaling or cAMP-PKA cascade was assessed in complete bronchi and in cultured epithelial cells. RESULTS: Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/ß-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535). Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization. Fenoterol exposure did not change the mRNA expression of genes regulating Wnt signaling or cAMP-PKA cascade. CONCLUSIONS: Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/ß-catenin pathway, suggesting a phenomenon of biased agonism in connection with the ß2-adrenoceptor stimulation. Future experiments based on the results of the present study will be needed to determine the impact of prolonged fenoterol exposure on the extra- and intracellular Wnt signaling pathways at the protein expression level.