Feasibility and efficacy of combined pancreatic islet-lung transplantation in cystic fibrosis-related diabetes-PIM study: A multicenter phase 1-2 trial.

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), and restoring metabolic control in these patients may improve their management after lung transplantation. In this multicenter, prospective, phase 1-2 trial, we evaluate the feasibility and metabolic efficacy of combined pancreatic islet-lung transplantation from a single donor in patients with CFRD, terminal respiratory failure, and poorly controlled diabetes. Islets were infused via the portal vein under local anesthesia, 1 week after lung transplantation. At 1 year, the primary outcome was transplant success as evaluated by a composite score including four parameters (weight, fasting glycemia, HbA1c, and insulin requirements). Ten participants (age: 24 years [17-31], diabetes duration: 8 years [4-12]) received a combined islet-lung transplant with 2892 IEQ/kg [2293-6185]. Transplant success was achieved in 7 out of 10 participants at 1-year post transplant. Fasting plasma C-peptide increased from 0.91 µg/L [0.56-1.29] to 1.15 µg/L [0.77-2.2], HbA1c decreased from 7.8% [6.5-8.3] (62 mmol/mol [48-67]) to 6.7% [5.5-8.0] (50 mmol/mol [37-64]), with 38% decrease in daily insulin doses. No complications related to the islet injection procedure were reported. In this pilot study, combined pancreatic islet-lung transplantation restored satisfactory metabolic control and pulmonary function in patients with CF, without increasing the morbidity of lung transplantation.

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.

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.

Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators.

Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆IscF/I+V) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. Isc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆IscF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆IscF/I+V response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

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.

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.

Techniques and results of lobar lung transplantations.

OBJECTIVES: We report our experience of lobar lung transplantations (LLTs) in patients with small thoracic volume. METHODS: Since 1988, 50 LLTs were done for cystic fibrosis (n=35), fibrosis (n=7), bronchiectasis (n=3), emphysema (n=3) and lymphangiomyomatosis (n=2). There were 44 females and 6 males (mean age 31±13 years, mean size 155±5.5 cm and mean predicted total lung capacity (TLC) 4463±598 ml). Mean ratio between donor and recipient-predicted TLC was 1.65±0.26. Six patients were listed in high emergency, 2 of them on ECMO as a bridge to transplantation. Forty middle/lower right lobe with left lower LLT, four bilateral lower LLT and six split left lung LLT were performed through a clamshell incision (n=12) or a bilateral antero-lateral thoracotomy (n=38), with epidural analgesia in 17 cases. Thirty-two patients were transplanted under circulatory support (CPB n=16, veno-arterial ECMO n=16). In 11 cases, the right venous anastomosis was enlarged by a pericardial cuff. Ischaemic time was 4.4±1.2 h for the first lobe and 6.1±1.3 h for the second. RESULTS: Median mechanical ventilation weaning time was 10.5 (1-136) days. Four patients were extubated in the operating room. Ten patients needed ECMO for primary graft dysfunction. In-hospital mortality was 28% related to sepsis (n=6), PGD (n=3), haemorrhage (n=2), broncho-vascular fistula (n=1), and multiorgan failure (n=2). Eight patients required endoscopic treatments for airway complications. Mean best FEV1 was 72±16% of the theoretical value. The actuarial 3-year and 5-year survival rates were 60 and 46%, respectively. CONCLUSIONS: LLTs are a reliable solution and can be performed with satisfactory functional results and survival rates.

An unidentified endobronchial object in a newly transplanted lung.

A fiberoptic examination is recommended at the end of lung transplantation for bronchial toilet and to check the bronchial anastomoses. This procedure permitted detection of a 10 × 4-mm piece of plastic of unknown origin in the left lingular bronchus and suggests that bronchoscopy should be performed before implanting the transplanted lung.

Efficacy of first-line chemotherapy in patients with advanced lung sarcomatoid carcinoma.

BACKGROUND: Sarcomatoid carcinomas (SCs) are rare tumors that may arise in the lung, accounting for 0.4% of non-small-cell lung cancers; the prognosis is poor. Only few retrospective small-size series have studied the efficacy of chemotherapy (CT) for metastatic SC. METHODS: Multicenter study of patients with advanced or metastatic SC who received first-line CT. Clinical characteristics at baseline, response to first-line CT (Response Evaluation Criteria in Solid Tumors version 1.1), progression-free survival (PFS), and overall survival (OS) were retrospectively collected. RESULTS: Ninety-seven patients were included. Median age was 62 (54-72) years. The majority of patients were men (70%), white (84%), and smokers (84%). Overall, 73% of patients received first-line platinum-based CT. At first tumor evaluation, 69% of patients experienced progression, 31% had disease control, and 16.5% had partial response. Partial response was observed in 20% of patients receiving platinum-based CT, and in none of those receiving non-platinum-based CT (p = 0.018). Median PFS was 2.0 months (confidence interval [CI] 95%: 1.8-2.3). PFS was not statistically different between patients receiving or not receiving a platinum-based CT. Median OS was 6.3 months (CI 95%: 4.7-7.8). There was a trend toward better OS for patients treated with platinum-based CT (7.0 months [CI 95%: 4.9-9.0] versus 5.3 months [CI 95%: 2.8-7.6]; p = 0.096). In multivariate analysis, disease control at first evaluation (hazard ratio = 0.38 [CI 95%: 0.21-0.59]) and at platinum-based CT (hazard ratio = 0.92 [CI 95%: 0.85-0.99]) was associated with better OS. CONCLUSION: SC is associated with poor prognosis and high rate of resistance to conventional first-line CT. New therapeutic strategies are needed, based on better knowledge of the carcinogenesis of SC.

[Sublobar curative resection for non-small-cell lung cancer]. / Résections carcinologiques limitées des cancers non à petites cellules du poumon.

It has been proved that lobectomy for lung cancer of less than 3 cm is superior to sublobar resection (segmentectomy and wedge resection) in the Lung Cancer Study Group trial published in 1995. Lobectomy is therefore recommended, with lymph node resection. Nevertheless, some publications have shown identical or close results after segmentectomy for tumors of less than 2 cm, and after wedge resection for tumors of less than 1 cm. It is likely that local recurrences are avoided by respecting a macroscopic margin of more than 2 cm around the tumor. A new trial comparing lobectomy and sublobar resection has been ongoing since 2007 for tumors of less than 2 cm. Persistent ground glass opacities are now often discovered after screening, either pure or with a small solid component, and correspond to an in situ or a micro-invasive adenocarcinoma, that can be removed with sublobar resection without recurrence.

Helical tomotherapy for resected malignant pleural mesothelioma: dosimetric evaluation and toxicity.

This study evaluated adjuvant helical tomotherapy after extrapleural pneumonectomy ± neo-adjuvant chemotherapy in 24 patients with malignant pleural mesothelioma. Toxicity was judged acceptable despite 2 cases (8%) of suspected grade 5 pneumonitis. With a mean follow-up of 7 months, 5 patients had distant and 2 local and distant failure.

Mesothelioma at era of helical tomotherapy: results of two institutions in combining chemotherapy, surgery and radiotherapy.

PURPOSE: There is a scarce clinical experience about adjuvant helical tomotherapy (HT) in patients affected by malignant pleural mesothelioma (MPM) even though it appears as a useful technique to treat complex volume as the pleural cavity, and seems to have better dose distribution than the "classic" intensity modulated radiotherapy (IMRT). METHODS AND MATERIALS: Twenty-four patients received adjuvant radiotherapy (RT) by HT from August 1st, 2007 to December 1st, 2009 at Curie Institute (Paris) and René Gauducheau Cancer Center (Nantes). Thirteen patients had neoadjuvant chemotherapy. Extrapleural pleuropneumonectomy (EPP) was done in 23 patients. Median dose to PTV was 50Gy [48.7-55.9Gy] (2Gy/fraction). Acute and long term toxicities, disease free survival (DFS), overall survival (OS) and relapses are presented. RESULTS: Average follow up after RT was 7 months. The disease was staged mostly as T2-T3, N1-N2. Nineteen patients had epithelial type histology. Most patients tolerated radiotherapy with grade 1-2 side effects: redness of the skin, light cough or dyspnea, fatigue, nausea and odynophagia, mild increase of the post-operative thoracic pain. Grade 3 pneumonitis was suspected in 2 patients. Two grade 5 pneumonitis were also suspected. Eleven patients had a follow up of more than 6 months and no long term side effects related with HT were noted. At 24 months, 51.8% of patients were free of disease. Thirty percent of patients relapsed, with 2 patients presenting local relapses. Two patients died from recurrence. CONCLUSION: With limited follow up, HT has comparable toxicity to those observed with traditional IMRT. Higher radiation dose and good coverage results in excellent local control.

Advances in lung transplantation for cystic fibrosis that may improve outcome.

OBJECTIVE: To study the advances in the management of lung-transplanted patients for cystic fibrosis in our centre and their impact on the outcome. METHODS: A retrospective study has included 100 patients who underwent lung transplantation for cystic fibrosis between 1 January 1990 and 15 January 2007. There were 78 sequential double-lung transplantations and 22 lobar transplantations. This series has been equally divided in two groups according to the date of transplantation: group I, before September 2003 and, group II, after September 2003. RESULTS: Recipient characteristics were similar in both groups. In group II, donors were older (40 vs 33 years, respectively, P=0.013), with lower partial pressure of oxygen in arterial blood (PaO(2))/fractional inspired oxygen (FiO(2)) ratios (372 vs 427 mmHg, P=0.022). In group II, recipients received, more often, thoracic epidural analgesia (n=35 vs n=13, P<0.001), the surgical approach was mostly a sternum-sparing bilateral anterior thoracotomy (n=42 vs n=9, P<0.001), and lobar transplantations were performed more frequently (n=15 vs n=7, P=0.30). Early tracheal extubation was more frequent in group II (P=0.005). The overall median survival time was 52 months. In the first group, 1-, 2- and 3-year survival rates were 75%, 65% and 55%, respectively, whereas in the second group, these survival rates were 88%, 78% and 69%, respectively (P=0.09). CONCLUSIONS: The acceptance of marginal donors and the frequent practice of lobar transplantations allowed an increasing number of lung transplantations for cystic fibrosis over time. Concomitantly, the extensive use of thoracic epidural analgesia has increased the rate of early extubation and contributed to a trend towards a survival improvement.

Single-lung transplantation in patients with previous contralateral pneumonectomy: technical aspects and results.

OBJECTIVE: Single-lung transplantation (SLTX) in patients with previous contralateral pneumonectomy (PN) is a rarely observed situation. Intrathoracic anatomical changes caused by mediastinal shift may complicate the surgical procedure. We collected observations from different transplantation centres to analyse the technical aspects and results. PATIENTS AND METHODS: Between July 1990 and September 2008, 14 patients (seven women and seven men) with previous PN underwent SLTX for end-stage pulmonary failure. Patients were categorised in three groups according to lung disease: cystic fibrosis bronchiectasis (group 1; n=4), non-cystic fibrosis bronchiectasis (group 2; n=6) and bronchioloalveolar carcinoma (group 3; n=4). We reviewed patients' characteristics according to mediastinal shift, thoracic approach, bypass cannula procedure, perioperative difficulties and immediate and long-term results. RESULTS: Median age was 19.5, 33.5 and 52.5 years in groups 1, 2 and 3, respectively; there were nine left and five right cases of SLTX. Surgery was performed by sternotomy (n=4), anterolateral thoracotomy (n=4), clamshell (n=4) or posterolateral thoracotomy (n=2). Cannulas for bypass were inserted into femoral (n=7) or central vessels (n=5) or both (n=2). Mediastinal shift did not complicate surgical procedure but rendered cannulation more difficult with ensuing cardiopulmonary bypass dysfunction (n=3) and early bronchial complications (n=2). In-hospital mortality rate was 29% (4 out of 14 patients), including two deaths due to perioperative difficulties linked to mediastinal shift. Median global survival was 108 months. Median survival was higher in group 2 (108 months vs 1 month in the other groups) and in case of PN during childhood (n=6, median survival 108 months corresponding to one death). CONCLUSIONS: SLTX after PN is associated with high perioperative morbidity and mortality due to mediastinal shift. Best results are observed in patients undergoing PN for non-cystic fibrosis bronchiectasis and during childhood. Anatomical changes induced by PN must be anticipated to adapt the thoracic approach and cardiopulmonary bypass access.

[Lung transplantation]. / Greffe pulmonaire.

Lung transplantation is now an effective therapy for patients of less than 60 years-old with chronic end-stage lung diseases which life expectancy is less than 12 to18 months in spite of maximal medical therapy. The various surgical procedures (single or bilateral lung or heart-lung transplantation) offer an adapted solution to all the candidates whatever the cause of the respiratory disease. The early postoperative mortality is less than 10% and the survival rates regularly improve and reach 65 to 7% at 3 years and more than 50% at 5 years for experienced programmes. Primary graft dysfunction, infections and airways complications are the main causes of early morbidity. Bronchiolitis obliterans is the main limiting factor of the long-term survival. Malignancies and drug toxicity, such as renal or vascular complications, occur also at that time.

Use of cardiopulmonary bypass for lung transplantation: a 10-year experience.

OBJECTIVE: The use of cardiopulmonary bypass (CPB) for lung transplantation (LTx) has been reported previously. This study reports the authors' experience of planned and unplanned use of cardiopulmonary bypass for LTx. DESIGN: Case series. SETTING: A university teaching hospital. PARTICIPANTS: Patients undergoing LTx. INTERVENTIONS: A retrospective analysis of the charts of all patients having undergone LTx over the last 10 years. MEASUREMENTS AND MAIN RESULTS: Among 140 LTx, 23 (16%) were performed with the use of CPB. CPB was planned in 11 cases and unplanned in the 12 other cases. The use of CPB is associated with a longer period of postoperative mechanical ventilation, more pulmonary edema, more blood transfusion requirement, and an increase in postoperative mortality at 48 hours and 1 month. Surgical difficulties related to the dissection of the native left lung and acute right ventricular failure are the main reasons for unscheduled use of CPB. CONCLUSION: Scheduled and unscheduled CPB for LTx are associated with an increased mortality at 1 month and 1 year.