Airway replacement using stented aortic matrices: Long-term follow-up and results of the TRITON-01 study in 35 adult patients.

Over the past 25 years, we have demonstrated the feasibility of airway bioengineering using stented aortic matrices experimentally then in a first-in-human trial (n = 13). The present TRITON-01 study analyzed all the patients who had airway replacement at our center to confirm that this innovative approach can be now used as usual care. For each patient, the following data were prospectively collected: postoperative mortality and morbidity, late airway complications, stent removal and status at last follow-up on November 2, 2021. From October 2009 to October 2021, 35 patients had airway replacement for malignant (n = 29) or benign (n = 6) lesions. The 30-day postoperative mortality and morbidity rates were 2.9% (n = 1/35) and 22.9% (n = 8/35) respectively. At a median follow-up of 29.5 months (range 1-133 months), 27 patients were alive. There have been no deaths directly related to the implanted bioprosthesis. Eighteen patients (52.9%) had stent-related granulomas requiring a bronchoscopic treatment. Ten among 35 patients (28.6%) achieved a stent free survival. The actuarial 2- and 5-year survival rates (Kaplan-Meier estimates) were respectively 88% and 75%. The TRITON-01 study confirmed that airway replacement using stented aortic matrices can be proposed as usual care at our center. Clinicaltrials.gov Identifier: NCT04263129.

Feasibility of Bioengineered Tracheal and Bronchial Reconstruction Using Stented Aortic Matrices.

Importance: Airway transplantation could be an option for patients with proximal lung tumor or with end-stage tracheobronchial disease. New methods for airway transplantation remain highly controversial. Objective: To establish the feasibility of airway bioengineering using a technique based on the implantation of stented aortic matrices. Design, Setting, and Participants: Uncontrolled single-center cohort study including 20 patients with end-stage tracheal lesions or with proximal lung tumors requiring a pneumonectomy. The study was conducted in Paris, France, from October 2009 through February 2017; final follow-up for all patients occurred on November 2, 2017. Exposures: Radical resection of the lesions was performed using standard surgical techniques. After resection, airway reconstruction was performed using a human cryopreserved (-80°C) aortic allograft, which was not matched by the ABO and leukocyte antigen systems. To prevent airway collapse, a custom-made stent was inserted into the allograft. In patients with proximal lung tumors, the lung-sparing intervention of bronchial transplantation was used. Main Outcomes and Measures: The primary outcome was 90-day mortality. The secondary outcome was 90-day morbidity. Results: Twenty patients were included in the study (mean age, 54.9 years; age range, 24-79 years; 13 men [65%]). Thirteen patients underwent tracheal (n = 5), bronchial (n = 7), or carinal (n = 1) transplantation. Airway transplantation was not performed in 7 patients for the following reasons: medical contraindication (n = 1), unavoidable pneumonectomy (n = 1), exploratory thoracotomy only (n = 2), and a lobectomy or bilobectomy was possible (n = 3). Among the 20 patients initially included, the overall 90-day mortality rate was 5% (1 patient underwent a carinal transplantation and died). No mortality at 90 days was observed among patients who underwent tracheal or bronchial reconstruction. Among the 13 patients who underwent airway transplantation, major 90-day morbidity events occurred in 4 (30.8%) and included laryngeal edema, acute lung edema, acute respiratory distress syndrome, and atrial fibrillation. There was no adverse event directly related to the surgical technique. Stent removal was performed at a postoperative mean of 18.2 months. At a median follow-up of 3 years 11 months, 10 of the 13 patients (76.9%) were alive. Of these 10 patients, 8 (80%) breathed normally through newly formed airways after stent removal. Regeneration of epithelium and de novo generation of cartilage were observed within aortic matrices from recipient cells. Conclusions and Relevance: In this uncontrolled study, airway bioengineering using stented aortic matrices demonstrated feasibility for complex tracheal and bronchial reconstruction. Further research is needed to assess efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT01331863.

Preliminary results in tracheal replacement using stented aortic matrices for primary extensive tracheal cancer.

Objective: Recent studies have demonstrated the feasibility and favorable long-term results of tracheobronchial replacement using stented cryopreserved aortic allografts. We propose to investigate the outcomes of this emerging technique in the subgroup of patients with extensive tracheal cancer. Methods: This study was based on 13 patients with primary extensive tracheal cancer extracted from the prospective registry TRITON-01 (ClinicalTrials.gov Identifier: NCT04263129), which included 40 patients in total. We analyzed early and late outcomes in this subset of patients. Results: From March 2019 to September 2022, 13 patients were included in the study. There were 9 female and 4 male patients, with a mean age of 53.9 years [36-71 years]. They had tracheal replacement for extended adenoid cystic carcinoma (n = 11), squamous cell carcinoma (n = 1), and mucoepidermoid carcinoma (n = 1). A venovenous extracorporeal membrane oxygenation was used in the 6 last cases. The mean length of resection was 81 mm [50-120 mm]. There was no 30-day postoperative mortality. A complete resection (R0) was achieved in 11 patients. The main late complications consisted of tracheal granulomas related to the stent and requiring repeated bronchoscopies (n = 9), pneumonia (n = 3), airway infection (n = 1), bronchoesophageal fistula (n = 1), mechanical stent obstruction requiring change (n = 2), and mediastinitis treated by antibiotics, drainage, and omentoplasty (n = 1). With a maximal follow-up of 3 years and 7 months, cancer recurrence was observed in 2 patients. All patients were alive at last follow-up except 2 (84.6%). Conclusions: Airway replacement using stented CAA represents a feasible and promising solution for extensive tracheal cancer.

[The lung]. / Le poumon.

Lung transplantation is still the only curative treatment for end-stage pulmonary diseases. The results remain poor, however, because of the limited availability of lung donors, chronic rejection, and complications related to immunosuppressive therapy. The use of a bioartificial lung generated from autologous cells could offer a solution. We have demonstrated that in vivo epithelial and cartilage regeneration of the airways is feasible with the use of an aortic tissue matrix. Other studies show that in vitro and in vivo airway regeneration, respectively, can be obtained by using bio-engineering and heterotopic allograft implantation. A more complex challenge is the creation of an artificial lung Indeed, this would require the use of an elastic matrix that can promote regeneration of the different lung components (airways, alveoli, vessels) over a large surface area, thus allowing ventilation, blood perfusion and gas exchanges. Recent studies have demonstrated the possibility of in vitro and in vivo regeneration of lung tissue from autologous cells, and especially stem cells. This emerging research field is currently dominated by the use of decellularized lung matrices and autologous epithelial and endothelial cells. Implantation of such a recellularized matrix in animals has proved the feasibility of a functional bio-artificial lung. The first human transplantation of a bio-artificial lung should be possible within 10-20 years.

Surgical resection of pulmonary inflammatory pseudotumors: long-term outcome.

Background Pulmonary inflammatory pseudotumors are rare lesions that remain problematic in several aspects, especially regarding the therapeutic strategy. The goal of this study was to evaluate long-term survival in a multicenter series of patients who required surgery for pulmonary inflammatory pseudotumors. Methods Thirty-six cases of pulmonary inflammatory pseudotumors, operated on in 3 French thoracic surgery departments between 1989 and 2015, were studied retrospectively. We recorded pre-, peri- and postoperative data for each patient, and long-term survival was analyzed. Results There were 22 men and 14 women. Mean age was 53.5 years (range 14-81 years). Three pneumonectomies, 1 bilobectomy, 19 lobectomies, 2 segmentectomies, 10 wedge resections, and 1 biopsy were performed. Complete resection was carried out in 32 (88.8%) patients. Median follow-up was 76 months. Five-year and 10-year survival rates were respectively 86.8% and 81.7% (96% and 90% for patients with R0 resection). Conclusions Long-term survival was excellent for patients with pulmonary inflammatory pseudotumors who benefited from surgery, especially when surgical resection was complete. These results confirm that surgical resection must be proposed as the first-line treatment for patients with pulmonary inflammatory pseudotumors.

In Vivo Tissue Engineering of Human Airways.

BACKGROUND: Airway transplantation remains a major challenge in thoracic surgery. Based on our previous laboratory work, we developed the techniques required to bioengineer a tracheal substitute in vivo using cryopreserved aortic allografts as biological matrices (Replacement of the Airways and/or the Pulmonary Vessels Using a Cryopreserved Arterial Allograft [TRACHEOBRONCART] Study, NCT01331863). We present here 2 patients who had a definitive tracheostomy for complex laryngotracheal stenoses refractory to conventional therapy. METHODS: According to our protocol, a stented gender-mismatched -80°C cryopreserved aortic allograft was used for airway reconstruction. Follow-up assessments were done at regular intervals using clinical, imaging, and endoscopic evaluations. Immunohistochemical and XX/XY chimerism studies were performed at time of stent removal using graft biopsy specimens. Chemotactic and angiogenic properties of implanted matrices were also investigated. RESULTS: At a maximal follow-up of 5 years and 7 months, the patients were breathing and speaking normally, without tracheostomy or stent. Regeneration of cartilage within the aortic grafts was demonstrated by positive immunodetection of type II collagen and markers specific for Sox9. Chimerism study from samples of neotissues demonstrated that regenerated cartilage came from recipient cells. The remaining viable matrix cells released a functionally relevant amount of proangiogenic, chemoattractant, proinflammatory/immunomodulatory cytokines, and growth factors. CONCLUSIONS: This report documents the feasibility of in vivo tissue engineering for long-term functional airway transplantation in humans.

Airway transplantation: a challenge for regenerative medicine.

After more than 50 years of research, airway transplantation remains a major challenge in the fields of thoracic surgery and regenerative medicine. Five principal types of tracheobronchial substitutes, including synthetic prostheses, bioprostheses, allografts, autografts and bioengineered conduits have been evaluated experimentally in numerous studies. However, none of these works have provided a standardized technique for the replacement of the airways. More recently, few clinical attempts have offered encouraging results with ex vivo or stem cell-based engineered airways and tracheal allografts implanted after heterotopic revascularization. In 1997, we proposed a novel approach: the use of aortic grafts as a biological matrix for extensive airway reconstruction. In vivo regeneration of epithelium and cartilage were demonstrated in animal models. This led to the first human applications using cryopreserved aortic allografts that present key advantages because they are available in tissue banks and do not require immunosuppressive therapy. Favorable results obtained in pioneering cases have to be confirmed in larger series of patients with extensive tracheobronchial diseases.

A more conservative technique for anterior mediastinal tracheostomy after sub-total resection of the trachea.

Anterior mediastinal tracheostomy (AMT) is a rare but challenging operation associated with a high morbidity and mortality rate mainly related to the invasiveness of the procedure. In order to provide a more conservative technique with a lower risk of major postoperative complications, we proposed: (1) to reduce the extent of chest wall resection to only a trapezoidal segment of the manubrium; (2) to use a simple pedicle pectoralis major flap instead of myocutaneous or omental flaps; and (3) to perform a simple relocation of the residual trachea (RT) below the brachiocephalic artery instead of artery ligation, percutaneous stent placement or replacement by cadaveric allograft. This technique was used in a patient with cancer recurrence at the cervical stoma after total laryngectomy. Despite a short 2.5-cm RT, it was possible to perform AMT without any tension at the mediastinal stoma. Postoperative course showed only regressive minor complications. There was no late complication related to the procedure with a one-year follow-up. This more conservative technique for AMT could be used as an alternative to previously described procedures in order to reduce postoperative complications and mortality rate after sub-total resection of the trachea.

Human transplantation of a biologic airway substitute in conservative lung cancer surgery.

BACKGROUND: Pneumonectomies for lung cancer are associated with a high postoperative mortality, especially when right-sided, after neoadjuvant radiochemotherapy, and in patients over 70 years of age. Preliminary studies in our laboratory have shown that aortic grafts could be valuable airway substitutes. We report the first human bronchial transplantation of a cryopreserved aortic allograft used as a biologic airway substitute to prevent a pneumonectomy for lung cancer. METHODS: The procedure was performed in a high-risk 78-year old patient with an extensive right bronchopulmonary malignant tumor pretreated with chemotherapy. After a complete resection of the lung cancer using an upper bilobectomy with lymph node removal, mobilization procedures did not allow for a primary end-to-end bronchial anastomosis. A stent-supported cryopreserved aortic allograft from a certified tissue bank was interposed to restore the bronchial continuity with sparing of the lower lobe. RESULTS: The postoperative course was eventful for a supraventricular arrhythmia leading to mild pulmonary edema that resolved using standard medical therapy, and a right lower lobe atelectasis with bacterial colonization that required fiberoptic bronchoscopies in addition to antibiotic treatment. A 1-year postoperative evaluation found a well-functioning reimplanted lower lobe with no complications related to the cryopreserved aortic allograft or the stent. The patient recovered to his baseline activity with a satisfying health-related quality of life. CONCLUSIONS: We demonstrate the feasibility of this surgical innovation to prevent the high-risk procedure of pneumonectomy in a single case. If confirmed in larger series of selected patients, it could bring new perspectives in conservative lung cancer surgery.

Bronchial replacement with arterial allografts.

BACKGROUND: Pneumonectomy is well known for a high risk of postoperative death. The alternative, sleeve lobectomy, is sometimes technically inaccessible, and is associated with locoregional recurrence. In certain situations, the use of a bronchial substitute would allow longer bronchial resections with better security margins. Previous experiments demonstrated that aortic grafts are valuable tracheal and carinal substitutes. The present study evaluated bronchial replacement with arterial allografts. METHODS: Fifteen female sheep underwent a left bilobectomy with replacement of the bronchus intermedius with arterial allografts: 5 received a fresh graft (group 1) and 10 received cryopreserved (group 2). A bronchial silicone stent was used to confer rigidity. Evaluation was conducted on clinical and histologic criteria at regular intervals up to 18 months. RESULTS: There were no perioperative deaths. Atelectasis, the only early postoperative complication (n = 2), was successfully treated by fiberscopic aspiration. The late postoperative period was uneventful in 12 sheep. Complications included 1 bronchopneumonia, 1 pulmonary abscess, and 1 distortion of the bronchial stent. Fiberscopic examination revealed 3 sheep with granuloma formation. The bronchial stent was removed in 3 sheep, 1 at 9 months and 2 at 12 months, without clinical complications or stenosis of the graft. Histologic analysis showed regeneration of new bronchial tissue, comprising epithelium and cartilage. CONCLUSIONS: This study confirmed that an arterial allograft could be a valuable bronchial substitute. The use of a bronchial substitute offers new perspectives in surgical resection of lung cancer because it would avoid pneumonectomy in some patients.

Postoperative pneumonia after major pulmonary resections: an unsolved problem in thoracic surgery.

BACKGROUND: Antibiotics currently recommended for prophylaxis in thoracic surgery are first-generation and second-generation cephalosporins. Despite this prophylaxis, postoperative pneumonia after major pulmonary resections remains frequent and severe. However, in the medical literature, the origin of these infections is poorly documented. METHODS: To evaluate the efficiency of current prophylactic regimens, we retrospectively analyzed 312 consecutive cases of major pulmonary resection, performed between January 2000 and December 2004. For patients who experienced postoperative pulmonary infection, the microbiologic agents and their antibiotic susceptibility were studied. RESULTS: A postoperative pneumonia was diagnosed in 76 patients (24.4% +/- 0.43%). Sixty patients (78.9%) experienced the infection in the first 5 postoperative days. A microbiologic documentation was obtained in 44 cases (57.9%) with 56 microorganisms involved. Pathogens responsible for the infections were Staphylococcus aureus (n = 10), Streptococcus pneumoniae (n = 8), group B Streptococcus organisms (n = 1), nongroupable Streptococcus organisms (n = 2), Enterococcus faecalis (n = 1), Haemophilus spp. (n = 9), Branhamella catarrhalis (n = 2), Enterobacteriaceae (n = 15), Pseudomonas aeruginosa (n = 3), Acinetobacter baumannii (n = 1), and Candida spp. (n = 4). According to the antibiotic susceptibility testings, the prophylactic regimen by cefazolin proved ineffective for 84% of the microbiologically documented cases. CONCLUSIONS: This study confirmed the inefficiency of current prophylaxis against pathogens involved in postoperative pneumonia after major lung resections. Evaluation of new and more-adapted approaches of antibiotic prophylaxis should be the subject of prospective multicenter trials.