The first tissue-engineered airway transplantation: 5-year follow-up results.

BACKGROUND: In 2008, the first transplantation of a tissue-engineered trachea in a human being was done to replace an end-staged left main bronchus with malacia in a 30-year-old woman. We report 5 year follow-up results. METHODS: The patient was followed up approximately every 3 months with multidetector CT scan and bronchoscopic assessment. We obtained mucosal biopsy samples every 6 months for histological, immunohistochemical, and electron microscopy assessment. We also assessed quality of life, respiratory function, cough reflex test, and production and specificity of recipient antibodies against donor human leucocyte antigen. FINDINGS: By 12 months after transplantation, a progressive cicatricial stenosis had developed in the native trachea close to the tissue-engineered trachea anastomosis, which needed repeated endoluminal stenting. However, the tissue-engineered trachea itself remained open over its entire length, well vascularised, completely re-cellularised with respiratory epithelium, and had normal ciliary function and mucus clearance. Lung function and cough reflex were normal. No stem-cell-related teratoma formed and no anti-donor antibodies developed. Aside from intermittent bronchoscopic interventions, the patient had a normal social and working life. INTERPRETATION: These clinical results provide evidence that a tissue-engineering strategy including decellularisation of a human trachea, autologous epithelial and stem-cell culture and differentiation, and cell-scaffold seeding with a bioreactor is safe and promising. FUNDING: European Commission, Knut and Alice Wallenberg Foundation, Swedish Research Council, ALF Medicine.

Malignant Solitary Fibrous Tumours of the Pleura Are Not All the Same: Analysis of Long-Term Outcomes and Evaluation of Risk Stratification Models in a Large Single-Centre Series.

Introduction: Malignant solitary fibrous tumours of the pleura (mSFTP) are extremely rare diseases (<5% of all pleural neoplasms) with unpredictable behaviour. Surgery remains the standard of care for these tumours; however, estimating patient prognosis and planning follow-up remain challenging. Several risk stratification models have been proposed, but a classification with diagnostic and prognostic potential has not been well standardised yet. The aim of this study was to analyse the clinicopathological data of mSFTP to investigate their prognostic features and to compare the performance of three risk stratification models proposed in the literature. Methods: Observational retrospective cohort study on all proven cases of mSFTP surgically resected with radical intent between 2000 and 2019 in a single centre. Demographic, surgical and pathological data were examined. All patients were risk-stratified by using three prediction models: modified Demicco, De Perrot and Tapias. Overall survival (OS) and disease-free survival (DFS) were analysed. Results: There were 21 men and 13 women (median age, 67 years, range, 23-83 years). Twenty-one patients (62%) were symptomatic. The median follow-up was 111 months (range, 6-258 months). The 5-year OS and DFS were 81.2% and 77.4%, respectively. Nine patients (26.5%) experimented recurrences. At univariate analysis, the presence of necrosis (p = 0.019), nuclear atypia (p = 0.006), dimension greater than 11.5 cm (median value of our cohort) (p = 0.037) and relapse/disease progression (p = 0.001) were independent prognostic factor of worse OS. The administration of adjuvant treatment was a protective independent factor for survival (p = 0.001). Radicality of resection (p = 0.005); tumour dimension (p = 0.013), presence of necrosis (p = 0.041) and nuclear atypia (p = 0.007) and pleural pattern (p = 0.011) were independent prognostic factors of worse DFS. Analysing the three risk stratification models, the Tapias score was revealed as the best index to predict both OS (p = 0.002) and DFS (p = 0.047) in patients with mSFTP. Conclusions: Using the risk stratification model proposed by Tapias, patients with the highest risk of recurrence could be identified at the time of surgery to establish a more frequent imaging surveillance and longer follow-up. The role of adjuvant treatment in mSFTP therapy has not been established yet, but further analysis on patients with a high risk of recurrence, stratified according to risk models, along with biomolecular panels may tailor future post-surgical therapies.

Which Surgery for Stage II-III Empyema Patients? Observational Single-Center Cohort Study of 719 Consecutive Patients.

OBJECTIVE: Recent guidelines support the use of thoracoscopic surgery in stage II-III empyema; however, there is still debate regarding the best surgical approach. The aim of our study is to compare postoperative outcomes of VATS and open surgical approaches for the treatment of post-pneumonic empyema. METHODS: Observational cohort study on prospectively collected cases of post-pneumonic empyema surgically treated in a single center (2000-2020). Patients were divided into an open group (OT, posterolateral muscle sparing thoracotomy) and VATS group (VT, 2 or 3 port ± utility incision). The primary outcome of the study was empyema resolution, assessed by the recurrence rate. Secondary outcomes were mortality, complications, pain and return to daily life. All patients were followed up at 1, 3 and 6 months after surgery in the outpatient clinic with a chest radiograph/CT scan. RESULTS: In total, 719 consecutive patients were surgically treated for stage II-III empyema, with 644 belonging to the VT group and 75 to the OT group. All patients had a clinical history of pneumonia lasting no more than 6 months before surgery, and 553 (76.9%) had stage II empyema. Operative time was 92.7 ± 6.8 min for the OT group and 112.2 ± 7.4 for the VT group. The conversion rate was 8.4% (46/545) for stage II and 19.2% (19/99) for stage III. Twelve patients (1.86%) in the VT group and four patients (5.3%) in the OT group underwent additional surgery for bleeding. Postoperative mortality was 1.25% (9/719): 5.3% (4/75) in OT and 0.77% (5/644) in VT. Postoperative stay was 10 ± 6.5 days in OT and 8 ± 2.4 in VT. Overall morbidity was 14.7% (106/719): 21.3% (16/75) in OT and 13.9% (90/644) in VT. In VT, six patients (0.93%) showed recurrent empyema: five were treated with chest drainage and one with additional open surgery. CONCLUSIONS: Our findings suggest that the VATS approach, showing a 99% success rate, shorter length of stay and lower postoperative morbidity, should be considered the treatment of choice for thoracic empyema.

Post-intubation tracheal lacerations: Risk-stratification and treatment protocol according to morphological classification.

Background: Post-intubation tracheal laceration (PITL) is a rare condition (0.005% of intubations). The treatment of choice has traditionally been surgical repair. Following our first report in 2010 of treatment protocol tailored to a risk-stratified morphological classification there is now clear evidence that conservative therapy represents the gold standard in the majority of patients. In this paper we aim to validate our risk-stratified treatment protocol through the largest ever reported series of patients. Methods: This retrospective analysis is based on a prospectively collected series (2003-2020) of 62 patients with PITL, staged and treated according to our revised morphological classification. Results: Fifty-five patients with Level I (#8), II (#36) and IIIA (#11) PITL were successfully treated conservatively. Six patients with Level IIIB injury and 1 patient with Level IV underwent a surgical repair of the trachea. No mortality was reported. Bronchoscopy confirmed complete healing in all patients by day 30. Statistical analysis showed age only to be a risk factor for PITL severity. Conclusions: Our previously proposed risk-stratified morphological classification has been validated as the major tool for defining the type of treatment in PITL.

Malignant Pleural Mesothelioma Nodal Status: Where Are We at?

Due to the lack of both prospective trial and high-volume retrospective studies, the management of clinical N+ malignant pleural mesothelioma (MPM) patients remains highly debated. Node positive patients show poor survival compared with node-negative ones; thus, lymph node staging appears crucial in determining treatment strategy. Notwithstanding the improvement in pre-treatment staging and the update on lymph node classification in the 8th edition of TNM, several open controversies remain on N parameter. How should we stage suspected N+ patients? How should we treat node positive patients? Which is the definition of a "resectable patient"? Is the site or the number the main prognostic factor for node positive patients? The aim of our narrative review is to analyse the existing relevant literature on lymph node status in MPM.

Hybrid treatment of T3 chest wall lung cancer lobectomy.

Nowadays the treatment of patients with non-small cell lung cancer (NSCLC) that invades the chest wall is still questioned. The classic approach is a lobectomy that requires chest wall resection through thoracotomy, but thanks to the progress in the field of thoracoscopic surgery, this procedure can be performed by video-assisted thoracoscopic surgery (VATS). Major advances have been made in recent years both in the surgical technique associated with thoracoscopy and in the instrumentation available today. This has allowed the use of thoracoscopic technique even in advanced disease. To choose to perform complex surgery in assisted video surgery, considerable experience is needed to avoid making mistakes and giving up a better approach for the patient only for any technical difficulties. Thoracoscopy is not currently the preferred intervention for patients with chest wall invasion because there are insufficient studies on the feasibility of lobectomy with thoracoscopic wall resection, although the thoracoscopic approach has reduced mortality and morbidity in lung cancer cases not in advanced stage. We discuss our experience in three patients using hybrid approach with assisted video thoracoscopic lobectomy and a chest wall en-block resection with an alternative method of estimating thoracic wall resection that uses assisted video surgery and hypodermic needles (minimally invasive posterior approach).

Local Control and Toxicity of Adaptive Radiotherapy Using Weekly CT Imaging: Results from the LARTIA Trial in Stage III NSCLC.

INTRODUCTION: Anatomical change of tumor during radiotherapy contributes to target missing. However, in the case of tumor shrinkage, adaptation of volume could result in an increased incidence of recurrence in the area of target reduction. This study aims to investigate the incidence of failure of the adaptive approach and, in particular, the risk for local recurrence in the area excluded after replanning. METHODS: In this prospective study, patients with locally advanced NSCLC treated with concomitant chemoradiation underwent weekly chest computed tomography simulation during treatment. In the case of tumor shrinkage, a new tumor volume was delineated and a new treatment plan outlined (replanning). Toxicity was evaluated with the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Patterns of failures were classified as in field (dimensional and/or metabolic progression within the replanning planning target volume [PTV]), marginal (recurrence in initial the PTV excluded from the replanning PTV), and out of field (recurrence outside the initial PTV). RESULTS: Replanning was outlined in 50 patients selected from a total of 217 patients subjected to weekly simulation computed tomography in our center from 2012 to 2014. With a median follow-up of 20.5 months, acute grade 3 or higher pulmonary and esophageal toxicity were reported in 2% and 4% of cases and late toxicity in 4% and 2%, respectively. Marginal relapse was recorded in 6% of patients, and 20% and 4% of patients experienced in-field and out-of-field local failure, respectively. CONCLUSIONS: The reduced toxicity and the documented low rate of marginal failures make the adaptive approach a modern option for future randomized studies. The best scenario to confirm its application is probably in neoadjuvant chemoradiation trials.

Does videomediastinoscopy with frozen sections improve mediastinal staging during video-assisted thoracic surgery pulmonary resections?

BACKGROUND: To assess if video-mediastinoscopy (VM) with frozen sections (FS) combined with a video-assisted thoracic surgery major pulmonary resection (VMPRS) is able to improve VATS mediastinal intraoperative staging. METHODS: From June 2012 to March 2015 a total of 146 patients underwent VMPRS lymphadenectomy. NCCN guidelines were followed for pre-operative staging, including VM with FS in 27 patients (19%). Procedural time, dissected nodal stations, complications related to VM and VATS lymphadenectomy and definitive histology, were evaluated. RESULTS: Operative time for VATS resection with VM (group 1) and VATS pulmonary resection alone (group 2) was 198±64 vs. 167±43 min (P=0.003). Mean/median numbers of dissected nodal stations were 4.93±1.1/5 (range, 4-8) in group 1 and 3.25±0.5/5 (range, 3-8) in group 2 (P<0.001). Group 1 vs. group 2 right-sided lymphadenectomy (n=86) was performed at station 2R/4R in 18 (90%) and 46 (69.7%); at station 3a/3p in 14 (51.8%) and 22 (31%); at station 7 in 18 (90%) and 44 (66.7%); at station 8/9 in 11 (55%) and 24 (36.4%) respectively. On the left side (n=60) group 1 vs. group 2 lymphadenectomy resulted at station 4 in 6 (85.7%) and 38 (71.7%); at station 5/6 in 6 (85.7%) and 26 (49%); at station 7 in 6 (85.7%) and 33 (62.3%), and at station 8/9 in 1 (14.3%) and 18 (34%). There were no early deaths and recurrent laryngeal nerve palsy occurred in 1 (0.8%) in group 2. Pathological upstaging (pN1; pN2) was found in 5 patients (17%) in group 1, and 13 (11%) in group 2 (P=0.23). About FS (n=29), formal paraffin histology resulted in 0% of both, false negative and false positive results. CONCLUSIONS: Based on our experience, the combination "VM with FS followed by VMPRS in sequence", seems to be effective and offers an alternative approach to improve intraoperative mediastinal staging.

Development of a video-assisted thoracoscopic lobectomy program in a single institution: results before and after completion of the learning curve.

BACKGROUND: The development of a video assisted thoracic surgery lobectomy (VATS-L) program provides a dedicated surgical team with a recognized learning curve (LC) of 50 procedures. We analyse the results of our program, comparing the LC with subsequent cases. METHODS: From June 2012 to March 2015, we performed n = 146 VATS major pulmonary resections: n = 50 (Group A: LC); n = 96 (Group B). Pre-operative mediastinal staging followed the National Comprehensive Cancer Network guidelines. All procedures were performed using a standard anterior approach to the hilum; lymphadenectomy followed the NCCN recommendations. During the LC, VATS-L indication was reserved to clinical stages I, therefore evaluated case by case. RESULTS: Mean operative time was 191 min (120-290) in Group A and 162 min (85-360) in Group B (p <0,01). Pathological T status was similar between two Groups. Lymphadenectomy included a mean of 5.8 stations in Group A and 6.6 in Group B resulting in: pN0 disease: Group A n = 44 (88 %), Group B n = 80 (83.4 %); pN1: Group A n = 3 (6 %), Group B n = 8 (8.3 %); pN2: Group A n = 3 (6 %), Group B n = 8 (8.3 %). Conversion rate was: 8 % in group A (n = 4 vascular injuries); 1.1 % in Group B (n = 1 hilar lymph node disease). We registered n = 6 (12 %) complications in Group A, n = 10 (10.6 %) in Group B. One case (1.1 %) of late post-operative mortality (90 days) was registered in Group B for liver failure. Mean hospital stay was 6.5 days in Group A and 5.9 days in Group B. CONCLUSIONS: We confirm the effectiveness of a VATS-L program with a learning curve of 50 cases performed by a dedicated surgical team. Besides the LC, conversion rate falls down, lymphadenectomy become more efficient, indications can be extended to upper stages.

Uniportal Videothoracoscopic Surgery: Our Indications and Limits.

OBJECTIVE: We present our experience with uniportal videothoracoscopic surgery (VATS-U), examining its indications, limits, and results. METHODS: Since January 2009, 66 patients underwent VATS-U for the following indications: pneumothorax (n = 25), lung nodule (n = 15; n = 10 with preoperative radiolocalization), wedge biopsy (n = 15), hyperhidrosis (n = 10), and chest wall schwannoma (n = 1). The conversion rate to conventional video-assisted thoracic surgery (VATS), postoperative pain, complications, residual paraesthesia, and hospitalization were analyzed. Operative time, postoperative pain, and paraesthesia were retrospectively compared with a cohort of 172 cases of conventional multiportal VATS, performed in the same period. RESULTS: Conversion to traditional VATS was necessary in two cases (pulmonary nodule, n = 1; pneumothorax, n = 1). The mean pain score was 0.8, the mean operation time was 42 minutes, and 10 patients had postoperative paraesthesia that lasted a mean of 7 days. No postoperative complications were reported, and the mean postoperative hospital stay was 3 days (range, 1-6 days). The comparison between the VATS-U and the standard multiportal VATS group showed in the VATS-U group a lower but not statistically significant pain score and paraesthesia as well as a lower and statistically significant operative time. CONCLUSIONS: Uniportal videothoracoscopic surgery has a wide range of indications: lung apex resections and pleurodesis for spontaneous pneumothorax treatment; pulmonary nodule assessment with or without preoperative localization; lung biopsy for interstitial diseases; unilateral or bilateral sympathectomy to treat hyperhidrosis; benign chest wall tumor evaluation. The limits of this technique are linked to pleural adhesions or lung nodules in difficult positions. In our experience, VATS-U results in minimal postoperative pain, allowing for fast functional recovery and a consequent short hospital stay; thus, we suggest that VATS-U is a valid alternative to traditional multiportal VATS for indications beyond cosmetic benefits. Prospective randomized trials are necessary to validate the advantages of uniportal VATS.

Carinal resection.

Carinal resections and reconstructions, with or without lung resection, are challenging operations that may be indicated in less than 1% of operable patients with NSCLC or benign lesions involving the carina. These operations are completed in only a few centers worldwide, likely because of their technical complexity and the general opinion about their limited patient benefit. However, good survival results can be expected in pN0 or pN1 patients so that, in experienced hands, these operations are effective options. The risk of postoperative complications can be minimized by several intraoperative and postoperative precautions.

Development and validation of a new outcome score in subglottic stenosis.

BACKGROUND: We prospectively evaluated a clinical and endoscopic score, the tracheal endoscopic clinical score (TECS), developed as a disease-specified outcome measure in adult patients undergoing operation for subglottic stenosis. We also performed a retrospective chart review to identify preoperative and intraoperative risk factors for worse TECS. METHODS: The TECS includes endoscopic (vocal cord and glottic function, anastomotic healing, and patency) and interview (respiration, voice, swallow) variables, and was administered at 6-month follow-up. Endoscopic and subjective domains were weighted to obtain a continuous TECS index ranging from 0 (best) to 1 (worse). The TECS and preoperative variables relationships were evaluated by univariate and multivariate analysis. RESULTS: We collected data (January 2009 to December 2010) from 30 patients (mean age, 48.3±19 years) undergoing subglottic resection and primary reconstruction. Stenosis etiology was postintubation (n=8), idiopathic (n=2), tracheostomy (n=18), and malignant (n=2). Surgery included Pearson operation with (n=7) or without (n=23) a Liberman-Mathisen cricoplasty. Mean length of resected trachea was 30.5±13.5 mm, and mean hospital stay was 7.4 days. Mortality rate was 1 patient (3.3%). The univariate analysis showed positive correlation between 6-month TECS and degree of stenosis (McCaffrey and Cotton scale 0 to 4) stage 4, tracheostomy or T-tube at surgery, bottleneck-type transition stenosis, and resection length. At multivariate analysis, the presence of tracheostomy, bottleneck-type transition stenosis and resection length were indicators of worse postoperative functional result. CONCLUSIONS: The TECS seems to be a valid and simple instrument to identify preoperative variables predicting worse results and to assess postoperative outcome. Validation on larger series is necessary.

Long-term changes to in vitro preserved bioengineered human trachea and their implications for decellularized tissues.

Bioengineered tissues created for transplant will be expected to survive and contribute to function over the lifetime of the individual. To evaluate potential intrinsic changes and degradation of the extracellular matrix of decellularized human tissue scaffolds, human decellularized tracheas were evaluated over a one year period in vitro. Human tracheas were decellularized and stored for one year in phosphate-buffered saline at 4 °C in the presence of antibiotics and anti-mycotics, and their structural, mechanical, and angiogenic properties compared to baseline values. Results showed that stored human decellularized tracheas were increasingly degraded resulting in a loss of extracellular matrix architecture - in particular of collagenous and elastic fiber structure -and decreased mechanical and angiogenic properties. The mechanical alterations of the extracellular matrix but not the deterioration and microstructure were not improved by using a natural cross-linking agent. These findings demonstrate that human decellularized tracheas, stored for one year in phosphate-buffered saline solution at 4 °C, would not meet the demands for a tissue engineering matrix and likely would not yield a suitable graft for lifelong implantation. The degradation phenomenon observed in vitro may be further enhanced in vivo, having clinical relevance for tissues that will be transplanted long-term and this should be carefully evaluated in pre-clinical settings.

The concept of in vivo airway tissue engineering.

We investigated whether decellularized pig tracheas could regenerate in vivo, without being recellularized before transplantation, using the own body as bioreactor. Decellularized pig tracheal scaffolds were intraoperative conditioned with mononuclear cells and growth and differentiation factors. During the postoperative period, the in situ regeneration was boosted by administering bioactive molecules to promote peripheral mobilization and differentiation of stem/progenitor cells and ultimately the regenerative process. Results revealed, after 2 weeks, a nearly normal trachea, with respiratory epithelium and a double-banded cartilage but without any mechanical differences compared to the native tissue. The growth factor administration resulted in a mobilization of progenitor and stem cells into the peripheral circulation and in an up-regulation of anti-apoptotic genes. Isolated stem/progenitor cells could be differentiated in vitro into several cell types, proving their multipotency. We provide evidence that the own body can be used as bioreactor to promote in vivo tissue engineering replacement. Moreover, we demonstrated the beneficial effect of additional pharmaceutical intervention for an improved engraftment of the transplant.

Development of bioengineered human larynx.

To date, only two human laryngeal allotransplants have been reported and, although they were successful, both patients required life-long immunosuppression. A bioengineered human larynx could represent a possible alternative to allotransplantation. Human larynxes were decellularized enzymatically to obtain acellular matrices. Histological and molecular analysis demonstrated that all cellular components and nuclear material were removed. SEM showed that decellularized matrices retained the hierarchical structures of the native larynx, and mechanical tests demonstrated that the decellularization did not significantly impaired the biomechanically properties of the obtained matrices. Immunohistochemical staining found residual angiogenic factors after decellularization, and CAM analysis demonstrated that acellular laryngeal scaffolds induce a strong in vivo angiogenic response. Using a decellularization method, we are now able to obtain, in a short and clinically useful time, natural bioengineered laryngeal scaffolds which could be use for partial or total implantation in humans.

Safety and effectiveness of a new fibrin pleural air leak sealant: a multicenter, controlled, prospective, parallel-group, randomized clinical trial.

BACKGROUND: This study evaluated the sealing capacity and safety of a new fibrin sealant (FS) to reduce alveolar air leaks (AALs) after pulmonary resections in a randomized controlled clinical trial conducted in 3 Italian centers. METHODS: The study randomized (1:1) 185 patients with an intraoperative AAL graded 1 to 3 according to the Macchiarini scale: 91 received FS and 94 had standard lung closure. The primary outcomes were the length of postoperative AAL duration and the mean time to chest drain removal. Other end points included the percentage of patients without AAL, the development of serum antibodies against bovine aprotinin, and any adverse event related to FS. Chest drains were removed when fluid output was 100 mL/day or less, with no air leak. RESULTS: The study groups were comparable with respect to demographic variables and surgical procedures. The FS group showed a statistically significant reduction in duration of postoperative AALs (9.52 vs 35.8 hours; p < 0.005) and in the percentage of patients with AALs at wound closure (81.11% vs 100%; p < 0.001); the difference in time to chest drain removal was not significant. Pleural empyema developed in 1 patient with FS treatment vs in 4 with standard treatment, and antibodies against bovine aprotinin were found in 34 of 91 FS-treated patients. CONCLUSIONS: The present study showed that the new FS is safe and effective in preventing AALs after lung resections and in shortening the duration of postoperative AALs.