Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH. METHODS AND RESULTS: Increased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH. CONCLUSION: This study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.

Voriconazole therapeutic drug monitoring among lung transplant recipients receiving targeted therapy for invasive aspergillosis.

BACKGROUND: Voriconazole is the first line treatment for invasive aspergillosis (IA) Current guidelines suggest performing regular voriconazole therapeutic drug monitoring (TDM) to optimize treatment efficacy. We aimed to determine if TDM was predictive of clinical outcome in LTRs. METHODS: Retrospective chart review was performed for all LTRs with probable or proven IA, treated with voriconazole monotherapy and who underwent TDM during therapy. Clinical outcome and toxicity were measured at 12 weeks. Classification and regression tree (CART) analysis was used to determine the most predictive voriconazole level thresholds for successful outcome. RESULTS: One hundred and eighteen TDM samples from 30 LTRs with IA were analyzed. Three LTRs were excluded due to early treatment discontinuation. The median TDM level was 1.2 µg/ml (range 0.06-7.3). At 12 weeks, 62% (17/27) of patients had a successful outcome, while 37% (10/27) of patients failed therapy. CART analysis determined that the best predictor for successful outcome was a median TDM level >0.72 µg/ml. Seventy percent (14/20) of patients with median TDM above 0.72 µg/ml had a successful outcome, compared to 42.9% (3/7) of patients with a median TDM below 0.72 µg/ml (OR 3.11; 95% CI: 0.53-20.4; P = 0.21). CART analysis determined that a TDM level greater than 2.13 µg/ml was predictive of hepatotoxicity. CONCLUSIONS: Our data suggests that a voriconazole TDM range between 0.72 µg/ml and 2.13 µg/ml may be associated with improved outcomes. Our study is in line with current recommendations on the use of voriconazole TDM in improving outcome and minimizing toxicity in LTR with IA.

Enhanced recovery after video-assisted thoracoscopic surgery lobectomy: a prospective, historically controlled, propensity-matched clinical study.

Background: Enhanced recovery pathways or fast-tracking following surgery can decrease the rate of postoperative complications and hospital length of stay. The objectives of this study were to implement an enhanced recovery after surgery (ERAS) pathway for patients undergoing a video-assisted thoracoscopic surgery (VATS) lobectomy, to assess the safety and efficiency of this protocol by measuring associated postoperative outcomes, and to compare the outcomes for patients in the ERAS group with the outcomes for patients in a propensity-matched control group. Methods: The study was a prospective clinical trial. Patients who were scheduled to undergo VATS lobectomy at the Centre hospitalier de l'Université de Montréal in Montréal, Quebec, Canada, were enrolled between November 2015 and October 2016. The ERAS pathway was used for all enrolled patients. The primary outcome was the number and severity of complications measured by the Comprehensive Complication Index. Secondary outcomes included length of stay, readmission and recovery. Recovery of patients was measured using EQ-5D-5L preoperatively and at 1 week, 1 month and 4 months after surgery. Prospectively enrolled patients were propensity matched to historical controls. Results: Ninety-eight patients (36 men and 62 women) in the ERAS group and 98 patients in the control group (29 men and 69 women) were included in the analysis. The mean age was 65.2 ± 9.3 years, the mean body mass index (BMI) was 26.9 ± 5.9 kg/m2 and the median Charlson Comorbidity Index score was 2 (interquartile range [IQR] 2-3) in the ERAS group. In the control group, the mean age was 66.2 ± 9.4 years, the mean BMI was 27.4 ± 5.6 kg/m2 and the median Charlson Comorbidity Index score was 3 (IQR 2-3). A total of 23 patients (23.4%) in the ERAS group and 28 (28.6%) in the control group experienced 1 or more postoperative complications. The mean Comprehensive Complication Index score was 7.4 ± 16.8 in the ERAS group compared with 8.0 ± 14.3 in the control group (p = 0.79). The median postoperative length of stay was 3 days in the ERAS group and 5 days in the control group (p < 0.001). Five patients in the ERAS group and 4 patients in the control group were readmitted. The protocol adherence rate was 64.3%. Conclusion: It is feasible to implement an enhanced recovery protocol after VATS lobectomy. Although the pathway is still early in its development in Canada, implementation of an ERAS pathway after VATS lobectomy was associated with decreased length of stay, with no observable increase in complication or readmission rates.

Contexte: Les protocoles de récupération optimisée, ou réhabilitation précoce, après une intervention chirurgicale permettent de réduire les taux de complications postopératoires et d'abréger le séjour hospitalier. Les objectifs de cette étude étaient d'appliquer les principes de récupération optimisée après une chirurgie (ou ERAS, enhanced recovery after surgery) à des patients soumis à une lobectomie par chirurgie thoracique vidéo-assistée (CTVA), d'évaluer l'innocuité et l'efficience d'un tel protocole en mesurant les paramètres postopératoires associés, et de comparer l'issue de l'intervention chez les patients du groupe ERAS à celle des patients d'un groupe témoin apparié par score de propension. Méthodes: Il s'agit d'un essai clinique prospectif. Des patients qui devaient subir une lobectomie par CTVA au Centre hospitalier de l'Université de Montréal, à Montréal, Québec, Canada, ont été recrutés entre novembre 2015 et octobre 2016. Les principes ERAS ont été appliqués à tous les patients inscrits. Le paramètre principal était le nombre et la gravité des complications mesurés à l'aide de l'Indice global de complications. Les paramètres secondaires incluaient la durée du séjour, les réadmissions et le rétablissement. Le rétablissement des patients a été mesuré à l'aide du questionnaire EQ-5D-5L avant, puis 1 semaine, 1 mois et 4 mois après la chirurgie. Les patients recrutés prospectivement ont été assortis à des témoins historiques par score de propension. Résultats: Au total, 98 patients (36 hommes et 62 femmes) du groupe ERAS et 98 patients du groupe témoin (29 hommes et 69 femmes) ont été inclus dans l'analyse. L'âge moyen était de 65,2 ± 9,3 ans, l'indice de masse corporelle (IMC) moyen était de 26,9 ± 5,9 kg/m2 et l'indice de comorbidité de Charlson médian était de 2 (éventail interquartile [ÉIQ] 2­3) dans le groupe ERAS. Dans le groupe témoin, l'âge moyen était de 66,2 ± 9,4 ans, l'IMC moyen était de 27,4 ± 5,6 kg/m2 et l'indice de comorbidité de Charlson médian était de 3 (ÉIQ 2­3). En tout, 23 patients (23,4 %) du groupe ERAS et 28 (28,6 %) du groupe témoin ont présenté au moins une complication postopératoire. L'Indice global de complications a été de 7,4 ± 16,8 dans le groupe ERAS, contre 8,0 ± 14,3 dans le groupe témoin (p = 0,79). La durée médiane du séjour postopératoire a été de 3 jours dans le groupe ERAS et de 5 jours dans le groupe témoin (p < 0,001). Cinq patients du groupe ERAS et 4 patients du groupe témoin ont été réadmis. Le taux d'adhésion au protocole a été de 64,3 %. Conclusion: Il est possible d'appliquer un protocole de récupération optimisée après la lobectomie par CTVA. Même si ce protocole en est encore à ses débuts au Canada, l'application de principes ERAS après la lobectomie par CTVA a été associée à un abrègement du séjour hospitalier, sans augmentation observable des taux de complications ou de réadmissions.

Double lung transplantation in an HIV-positive patient with Mycobacterium kansasii infection.

Good outcomes with kidney and liver transplantation in HIV-positive patients have led clinicians to recommend lung transplantation in HIV-positive patients based on extrapolated data. Pre-transplant mycobacterial infection is associated with an increased risk of developing new infection or aggravating existing infection, though it does not contraindicate transplantation in non-HIV-infected patients. However, no data exists regarding the outcome of HIV-positive patients with pre-transplant mycobacterial infection. We report a case of double lung transplantation in a 50-year-old HIV-positive patient with alpha-1 antitrypsin deficiency. Prior to transplantation, Mycobacterium kansasii was isolated in one sputum culture and the patient was considered merely colonized as no clinical evidence of pulmonary or disseminated disease was present. The patient successfully underwent a double lung transplantation. Nontuberculous mycobacterial infection was diagnosed histologically on examination of native lungs. Surveillance and watchful waiting were chosen over treatment of the infection. HIV remained under control post-transplantation with no AIDS-defining illnesses throughout the follow-up. A minimal acute rejection that responded to increased corticosteroids was reported. At 12 months post-transplant, a bronchiolitis obliterans syndrome was diagnosed after a drop in FEV1. No evidence of isolation nor recurrence of nontuberculous mycobacteria was reported post-transplantation. At 15 months post-transplant, the patient remained stable with an FEV1 of 30%. The presence of pre-transplant nontuberculous mycobacterial infection did not translate into recurrence of nontuberculous mycobacterial infection post-transplant. Whether it contributed to bronchiolitis obliterans syndrome remains unknown.

Transtracheal thoracic natural orifice transluminal endoscopic surgery (NOTES) in a swine model.

BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) has the potential to be the final frontier in minimally invasive procedures in thoracic surgery. In order for thoracic pleural NOTES to 1 day be ready for clinical trials, each step of the procedure must be independently evaluated for both safety and efficacy. The aim of this study was to evaluate the trachea as a portal of entry for thoracic NOTES. METHODS: Eight 40-kg swine underwent right thoracic pleuroscopy in a survival model. In order to avoid inadvertent injury to the superior vena cava, endobronchial ultrasound was employed to select the location of airway incision. A 7-mm linear incision was then performed at the chosen location using an endoscopic electrocautery needle knife through a therapeutic flexible videobronchoscope. The mediastinal fat and parietal pleura were then dissected with electrocautery, and complete right pleuroscopy was performed. The tracheal and mediastinal portal of entry were then sealed with 1-2 cc of fibrin sealant. The pigs were kept alive for 21 days postoperatively. Postmortem diagnostic bronchoscopy was performed to assess tracheal healing. All tracheal specimens underwent histologic examination for healing and signs of mediastinal infection. RESULTS: Thoracic NOTES procedures on all eight pigs were successful. There were no intraoperative complications except for one minor bleeding episode within the mediastinal dissection site which stopped spontaneously. Two pigs died from severe laryngospasm in the early postoperative period. Six pigs survived for 21 days post-procedure and experienced uneventful postoperative courses. Postmortem examination demonstrated complete tracheal healing with appropriate scarring in all pigs. CONCLUSIONS: The trachea appears to be a safe port of entry for thoracic NOTES procedures in a swine model. Smaller tracheal incisions followed by balloon dilatation are associated with less postoperative morbidity and mortality. Tracheal incisions sealed with fibrin sealant healed rapidly and without signs of mediastinal infection. This procedure represents a work in progress and is not yet ready for human trials.

Human basophils interact with memory T cells to augment Th17 responses.

Basophils are a rare population of granulocytes that have long been associated with IgE-mediated and Th2-associated allergic diseases. However, the role of basophils in Th17 and/or Th1 diseases has not been reported. In the present study, we report that basophils can be detected in the mucosa of Th17-associated lung and inflammatory bowel disease and accumulate in inflamed colons containing large quantities of IL-33. We also demonstrate that circulating basophils increased memory Th17 responses. Accordingly, IL-3- or IL-33-activated basophils amplified IL-17 release in effector memory T cells (T(EM)), central memory T cells (T(CM)), and CCR6(+) CD4 T cells. More specifically, basophils promoted the emergence of IL-17(+)IFN-γ(-) and IL-17(+)IFN-γ(+), but not IL-17(-)IFN-γ(+) CD4 T cells in T(EM) and T(CM). Mechanistic analysis revealed that the enhancing effect of IL-17 production by basophils in T(EM) involved the ERK1/2 signaling pathway, occurred in a contact-independent manner, and was partially mediated by histamine via H(2) and H(4) histamine receptors. The results of the present study reveal a previously unknown function for basophils in augmenting Th17 and Th17/Th1 cytokine expression in memory CD4 T cells. Because basophils accumulated in inflamed inflammatory bowel disease tissues, we propose that these cells are key players in chronic inflammatory disorders beyond Th2.

Defining Optimal Settings for Lung Cryobiopsy in End-Stage Pulmonary Disease. A Human, Ex Vivo, Diseased Lung Clinical Trial.

BACKGROUND: To evaluate optimal settings of probe size, freezing time, and distance to the pleura that influence the size and quality of biopsy specimens during transbronchial lung cryobiopsies in ESPD. METHODS: We prospectively recruited 17 patients undergoing lung transplantation. We created a nonperfused ex vivo bronchoscopy setting to perform multiple cryobiopsies with different probe sizes (1.7, 1.9, and 2.4 mm), freezing times (3, 5, 7, 10, 20, 30 seconds), and probe distance from pleura (5, 10, and 20 mm). Alveolated pulmonary parenchyma area≥50% in histology was considered a good quality biopsy, with a minimum procedural artifact. We used logistic regression to identify independent parameters as risk factors for histologic adequacy. RESULTS: A total of 545 cryobiopsies were obtained from 34 explanted lungs after pneumonectomy for lung transplantation. The mean maximum diameter of the specimen achieved with the 1.7 probe was larger (13.5 mm) than those obtained with 1.9 and 2.4 mm probes (11.3 and 10.7 mm, P= 0.07). More pleural macroscopic damage and pleural tissue in histology occurred with the 2.4 mm probe ( P <0.001). There was no difference in the quality of specimens between the different freezing times and the distance from the pleura. CONCLUSIONS: Freezing time and distance from the pleura did not affect the histologic quality for diagnosing ESPD in severely damaged lungs. Smaller cryoprobe size did not negatively affect sample adequacy.

Impact of Transplant Body Mass Index and Post-Transplant Weight Changes on the Development of Chronic Lung Allograft Dysfunction Phenotypes.

INTRODUCTION: Chronic lung allograft dysfunction (CLAD) is a lung transplant complication for which four phenotypes are recognized: Bronchiolitis obliterans syndrome (BOS), Restrictive allograft syndrome (RAS), mixed and undefined phenotypes. Weight gain is common after transplant and may negatively impact lung function. Study objectives were to describe post-transplant weight trajectories of patients who developed (or did not) CLAD phenotypes and examine the associations between BMI at transplant, post-transplant changes in weight and BMI, and the risk of developing these phenotypes. METHODS: Adults who underwent a bilateral lung transplant between 2000 and 2020 at our institution were categorized as having (or not) one of the four CLAD phenotypes based on the proposed classification system. Demographic, anthropometric, and clinical data were retrospectively collected from medical records and analyzed. RESULTS: Study population included 579 recipients (412 [71.1%] CLAD-free, 81 [14.0%] BOS, 20 [3.5%] RAS, 59 [10.2%] mixed, and 7 [1.2%] undefined phenotype). Weight gains of greater amplitude were seen in recipients with restrictive phenotypes than CLAD-free and BOS patients within the first five years post-transplant. While the BMI category at transplant was not statistically associated with the risk of developing CLAD phenotypes, an increase in weight (Hazard ratio [HR]: 1.04, 95% CI [1.01-1.08]; P = .008) and BMI (HR: 1.13, 95% CI [1.03-1.23]; P = .008) over the post-transplant period was associated with a greater risk of RAS. CONCLUSION: Post-LTx gain in weight and BMI modestly increased the risk of RAS, adding to the list of unfavorable outcomes associated with weight gain following transplant.

Intersurgeon variations in postoperative length of stay after video-assisted thoracoscopic surgery lobectomy.

Objectives: To identify factors associated with prolonged postoperative length of stay (LOS) after VATS lobectomy (VATS-L), explore potential intersurgeon variation in LOS and ascertain whether or not early discharge influences hospital readmission rates. Methods: We conducted a retrospective analysis of patients who underwent VATS-L at a single academic center between 2018 and 2021. Each VATS lobectomy procedure was performed by 1 of 7 experienced thoracic surgeons. The primary end point of interest was prolonged LOS, defined as an index LOS >3 days. Results: Among 1006 patients who underwent VATS lobectomy, 632 (63%) had a prolonged LOS. On multivariate analysis, the factors independently associated with prolonged LOS were: surgeon (P < .001), patient age (odds ratio [OR], 1.03; 95% CI, 1.02-1.06), operation time (OR, 1.01; 95% CI, 1.01-1.01), postoperative complication (OR, 3.60; 95% CI, 2.45-5.29), and prolonged air leak (OR, 8.95; 95% CI, 4.17-19.23). There was no significant association between LOS and gender, body mass index, coronary artery disease, prior atrial fibrillation, American Society of Anesthesiologists score >3, and prior ipsilateral thoracic surgery or sternotomy. There was no association between LOS ≤3 days and hospital readmission (20 [5.3%] vs 39 [5.9%]; OR, 0.88; 95% CI, 0.50-1.53). Conclusions: An intersurgeon variation in postoperative LOS after VATS-L exists and is independent of patient baseline characteristics or perioperative complications. This variation seems to be more closely related to differences in postoperative management and discharge practices rather than to surgical quality. Postoperative discharge within 3 days is safe and does not increase hospital readmissions.

Randomized trial of routine versus on-demand intraoperative extracorporeal membrane oxygenation in lung transplantation: A feasibility study.

In most centers, extracorporeal membrane oxygenation (ECMO) is the preferred means to provide cardiopulmonary support during lung transplantation. However, there is controversy about whether intraoperative venoarterial (VA) ECMO should be used routinely or selectively. A randomized controlled trial is the best way to address this controversy. In this publication, we describe a feasibility study to assess the practicality of a protocol comparing routine versus selective VA-ECMO during lung transplantation. This prospective, single-center, randomized controlled trial screened all patients undergoing lung transplantation. Exclusion criteria include retransplantation, multiorgan transplantation, and cases where ECMO is mandatory. We determined that the trial would be feasible if we could recruit 19 participants over 6 months with less than 10% protocol violations. Based on the completed feasibility study, we conclude that the protocol is feasible and safe, giving us the impetus to pursue a multicenter trial with little risk of failure due to low recruitment.

Right Ventricular Assist Device With an Oxygenator for the Management of Combined Right Ventricular and Respiratory Failure: A Systematic Review.

BACKGROUND: Severe lung disease frequently presents with both refractory hypoxemia and right ventricular (RV) failure. Right ventricular assist device with an oxygenator (OxyRVAD) is an extracorporeal membrane oxygenation (ECMO) configuration of RV bypass that also supplements gas exchange. This systematic review summarises the available literature regarding the use of OxyRVAD in the setting of severe lung disease with associated RV failure. METHODS: PubMed, Embase, and Google Scholar were queried on September 27, 2023, for articles describing the use of an OxyRVAD configuration. The main outcome of interest was survival to intensive care unit (ICU) discharge. Data on the duration of OxyRVAD support and device-related complications were also recorded. RESULTS: Out of 475 identified articles, 33 were retained for analysis. Twenty-one articles were case reports, and 12 were case series, representing a total of 103 patients. No article provided a comparison group. Most patients (76.4%) were moved to OxyRVAD from another type of mechanical support. OxyRVAD was used as a bridge to transplant or curative surgery in 37.4% and as a bridge to recovery or decision in 62.6%. Thirty-one patients (30.1%) were managed with the dedicated single-access dual-lumen ProtekDuo cannula. Median time on OxyRVAD was 12 days (interquartile range 8-23 days), and survival to ICU discharge was 63.9%. Device-related complications were infrequently reported. CONCLUSION: OxyRVAD support is a promising alternative for RV support when gas exchange is compromised, with good ICU survival in selected cases. Comparative analyses in patients with RV failure with and without severe lung disease are needed.

Cystic fibrosis transmembrane conductance regulator is expressed in mucin granules from Calu-3 and primary human airway epithelial cells.

Cystic fibrosis (CF) is caused by mutations in the tightly regulated anion channel cystic fibrosis transmembrane conductance regulator (CFTR), yet much of the pathology in this disease results from mucus obstruction of the small airways and other organs. Mucus stasis has been attributed to the abnormal luminal environment of CF airways, which results from dehydration of the mucus gel or low bicarbonate concentration. We show here that CFTR and MUC5AC are present in single mucin-containing granules isolated from a human airway epithelial cell line and from highly differentiated airway primary cell cultures. CFTR was not detected in MUC5AC granules from CFTR knockdown cells or CF primary cells. The results suggest a direct link between CFTR and the mucus defect.

Induction of nitric oxide synthase expression by lipopolysaccharide is mediated by calcium-dependent PKCα-ß1 in alveolar epithelial cells.

Nitric oxide (NO) plays an important role in innate host defense and inflammation. In response to infection, NO is generated by inducible nitric oxide synthase (iNOS), a gene product whose expression is highly modulated by different stimuli, including lipopolysaccharide (LPS) from gram-negative bacteria. We reported recently that LPS from Pseudomonas aeruginosa altered Na⁺ transport in alveolar epithelial cells via a suramin-dependent process, indicating that LPS activated a purinergic response in these cells. To further study this question, in the present work, we tested whether iNOS mRNA and protein expression were modulated in response to LPS in alveolar epithelial cells. We found that LPS induced a 12-fold increase in iNOS mRNA expression via a transcription-dependent process in these cells. iNOS protein, NO, and nitrotyrosine were also significantly elevated in LPS-treated cells. Ca²âº chelation and protein kinase C (PKCα-ß1) inhibition suppressed iNOS mRNA induction by LPS, implicating Ca²âº-dependent PKC signaling in this process. LPS evoked a significant increase of extracellular ATP. Because PKC activation is one of the signaling pathways known to mediate purinergic signaling, we evaluated the hypothesis that iNOS induction was ATP dependent. Although high suramin concentration inhibited iNOS mRNA induction, the process was not ATP dependent, since specific purinergic receptor antagonists could not inhibit the process. Altogether, these findings demonstrate that iNOS expression is highly modulated in alveolar epithelial cells by LPS via a Ca²âº/PKCα-ß1 pathway independent of ATP signaling.

Post-Operative Outcomes Associated With Open Versus Robotic Thymectomy: A Propensity Matched Analysis.

To compare post-operative outcomes associated with thymectomy performed using either open or robotic approaches. Retrospective cohort study from a single-center prospective registry consisting of patients undergoing thymectomy between 2000 and 2020. Patients were grouped according to surgical approach (open vs robotic). A propensity-score matching analysis was performed in a 2:1 open to robotic ratio, and surgical outcomes were evaluated. We analyzed 234 thymectomies (155 open; 79 robotic). Myasthenia gravis was present in 23.2% and 32.9% (P = 0.249) in the open and in the robotic group, respectively. All covariates were balanced in the matched groups (open n = 114; robotic n =5 9), except lesion size. The robotic approach was significantly associated with shorter surgical time (median 95 vs 65 minutes, P < 0.001), lesser clinical (21.1% vs 6.8%, P = 0.016) and surgical (11.4% vs 1.7%, P = 0.036) complications during the same hospitalization, less Clavien-Dindo grade 2 or higher complication rates (28.1 vs 15.3%, P = 0.048), chest tube duration (median: 3 vs 0 days, P < 0.001) and in-hospital length of stay (median: 5 vs 0 days, P < 0.001). Bleeding (P = 0.214), ICU length of stay (P = 0.167), reoperation rate (open, 1.8% vs robotic 0%), 90-day mortality (P = 0.341) and readmission rate post discharge (P = 0.277) were similar between the groups. In the matched population with primary thymic epithelial tumors, the completeness of resection rate was similar (open, 92.1% vs robotic 96.8%, P = 0.66.). Robotic thymectomy is associated with improved post-operative outcomes when compared to open thymectomy, without compromising the goals of oncologic surgery. Longer follow-up is needed to ensure oncologic equivalence.

Outside the Cage Subcostal RATS Lobectomy: Technical Aspects and Results of the First Series of a Novel Approach to Pulmonary Lobectomy.

OBJECTIVE: The goal of minimally invasive surgery is to reduce trauma to patients and improve their postoperative outcomes. In this context, the utilization of robot-assisted thoracic surgery (RATS) in the treatment of lung cancer has increased worldwide. The feasibility of single-incision major pulmonary resections by RATS was recently reported, with the objective of minimizing the surgical trauma of the traditional multiportal RATS approach. However, both techniques require intercostal incisions, potentially causing immediate and chronic pain resulting from intercostal nerve injury. To reduce postoperative pain resulting from intercostal approaches, we developed a nonintercostal, outside the thoracic cage (OTC) approach for RATS lobectomy, avoiding intercostal instrumentation. This report aims to describe the results of the first reported series of OTC subcostal RATS lobectomies. METHODS: Retrospective analysis of a series of the first consecutive patients operated on using the novel OTC subcostal RATS lobectomy technique. RESULTS: Between August and December 2022, a total of 10 consecutive cases were analyzed. The median age was 63 (55 to 84) years, the mean body mass index was 29 (24 to 45) kg/m2, and the median American Society of Anesthesiologists score was III (II to IV). No serious adverse events were observed, and there was no conversion of the surgical technique. The mean operative time was 132.6 (98 to 223) min. The median length of stay was 2 days. No pain-related complications, readmissions, or 30-day mortality were observed. CONCLUSIONS: This series demonstrates that OTC RATS lobectomy is feasible and safe. A phase I clinical trial is currently underway to prospectively assess the safety of the technique as well as its clinical relevance.

Post-transplant outcomes among cystic fibrosis patients undergoing lung transplantation colonized by Burkholderia: A single center cohort study.

BACKGROUND: Prior infection with Burkholderia cepacia complex (BCC) has been associated with poorer outcomes after lung transplantation, posing an important dilemma for cystic fibrosis (CF). Although current guidelines consider BCC infection to be a relative contraindication, some centers continue to offer lung transplantation to BCC-infected CF patients. METHODS: We conducted a retrospective cohort study which included all consecutive CF-LTR between 2000 and 2019 to compare the postoperative survival of BCC-infected CF lung transplant recipients (CF-LTR) to BCC-uninfected patients. We used a Kaplan-Meier analysis to compare survival of BCC-infected to BCC-uninfected CF-LTR and fitted a multivariable Cox model, adjusted for age, sex, BMI and year of transplantation as potential confounders. As an exploratory analysis, Kaplan-Meier curves were also stratified by the presence of BCC and urgency of transplantation. RESULTS: A total of 205 patients were included with a mean age of 30.5 years. Seventeen patients (8%) were infected with BCC prior to LT. Patients were infected with the following species: B. multivorans5, B. vietnamiensis3, combined B. multivorans and B. vietnamiensis3 and others4. None of the patients were infected with B. cenocepacia. Three patients were infected with B. gladioli. One-year survival was 91.7% (188/205) for the entire cohort, 82.4% (14/17) among BCC-infected CF-LTR, and 92.5% (173/188) among BCC uninfected CF-LTR (crude HR = 2.19; 95%CI 0.99-4.85; p = 0.05). In the multivariable model, presence of BCC was not significantly associated with worse survival (adjusted HR 1.89; 95%CI 0.85-4.24; p = 0.12). In the stratified analysis for both presence of BCC and urgency of transplantation, urgency of transplantation among BCC-infected CF-LTR appeared to be associated with poorer outcome (p = 0.003 across the 4 subgroups). CONCLUSION: Our results suggest that non-cenocepacia BCC-infected CF-LTR have comparable survival rate to BCC-uninfected CF-LTR.

Improvement of defective cystic fibrosis airway epithelial wound repair after CFTR rescue.

Airway damage and remodelling are important components of lung pathology progression in cystic fibrosis (CF). Although repair mechanisms are engaged to restore the epithelial integrity, these processes are obviously insufficient to maintain lung function in CF airways. Our aims were therefore to study how the basic cystic fibrosis transmembrane conductance regulator (CFTR) defect could impact epithelial wound healing and to determine if CFTR correction could improve it. Wound-healing experiments, as well as cell migration and proliferation assays, were performed to study the early phases of epithelial repair in human CF and non-CF airway cells. CFTR function was evaluated using CFTR small interferring (si)RNA and inhibitor GlyH101 in non-CF cells, and conversely after CFTR rescue with the CFTR corrector VRT-325 in CF cells. Wound-healing experiments first showed that airway cells from CF patients repaired slower than non-CF cells. CFTR inhibition or silencing in non-CF primary airway cells significantly inhibited wound closure. GlyH101 also decreased cell migration and proliferation. Interestingly, wild-type CFTR transduction in CF airway cell lines or CFTR correction with VRT-325 in CFBE-ΔF508 and primary CF bronchial monolayers significantly improved wound healing. Altogether our results demonstrated that functional CFTR plays a critical role in wound repair, and CFTR correction may represent a novel strategy to promote the airway repair processes in CF.

Enhanced Ca2+ entry due to Orai1 plasma membrane insertion increases IL-8 secretion by cystic fibrosis airways.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, causes retention of CFTR in the endoplasmic reticulum (ER). Some CF abnormalities can be explained by altered Ca(2+) homeostasis, although it remains unknown how CFTR influences calcium signaling. This study examined the novel hypothesis that store-operated calcium entry (SOCE) through Orai1 is abnormal in CF. The significance of Orai1-mediated SOCE for increased interleukin-8 (IL-8) expression in CF was also investigated. CF and non-CF human airway epithelial cell line and primary cells (obtained at lung transplantation) were used in Ca(2+) imaging, electrophysiology, and fluorescence imaging experiments to explore differences in Orai1 function in CF vs. non-CF cells. Protein expression and localization was assessed by Western blots, cell surface biotinylation, ELISA, and image correlation spectroscopy (ICS). We show here that store-operated Ca(2+) entry (SOCE) is elevated in CF human airway epithelial cells (hAECs; ≈ 1.8- and ≈ 2.5-fold for total Ca(2+)(i) increase and Ca(2+) influx rate, respectively, and ≈ 2-fold increase in the I(CRAC) current) and is caused by increased exocytotic insertion (≈ 2-fold) of Orai1 channels into the plasma membrane, which is normalized by rescue of ΔF508-CFTR trafficking to the cell surface. Augmented SOCE in CF cells is a major factor leading to increased IL-8 secretion (≈ 2-fold). CFTR normally down-regulates the Orai1/stromal interaction molecule 1 (STIM1) complex, and loss of this inhibition due to the absence of CFTR at the plasma membrane helps to explain the potentiated inflammatory response in CF cells.

Impact of Volume on Mortality and Hospital Stay After Lung Cancer Surgery in a Single-Payer System.

BACKGROUND: There is a literature gap for hospitals in single-payer health care systems quantifying the influence of hospital volume on outcomes after major lung cancer resection. We aimed to determine the effect of hospital volume on mortality and length of stay. METHODS: A retrospective cohort study using administrative, population-based data from a single-payer universal health care system was performed in adults with non-small cell lung cancer who underwent lobectomy or pneumonectomy between 2008 and 2017. Hospital volume was defined as the average annual number of major lung resections performed at each institution. Length of stay and postoperative mortality were compared using multivariable linear and nonlinear regression between hospital volume categories and continuously. Adjusted association between hospital volume and postoperative mortality was determined by multivariable logistic regression. RESULTS: In all, 10 831 lung resections were performed: 1237 pneumonectomies and 9594 lobectomies. Patients undergoing lobectomy at high-volume hospitals had shorter median length of stay (6 vs 8 days, P = .001) compared with low-volume hospitals. After adjusting for confounders, surgery at a high-volume center was significantly associated with shorter length of stay after lobectomy and overall resections (P ≤ .001), but not after pneumonectomy (P = .787). Surgery at a high-volume center was positively associated with improved 90-day mortality in lobectomy and overall procedures (odds ratio 0.607 [95% confidence interval, 0.399 to 0.925], and 0.632 [95% confidence interval, 0.441 to 0.904], respectively). Volume was not a predictor of 90-day mortality after pneumonectomy (odds ratio 0.533 [95% confidence interval, 0.257 to 1.104], P = .090). CONCLUSIONS: Surgery at a high-volume center was positively correlated with improved 90-day survival and shorter hospital length of stay. The results support regionalized lung cancer care in a single-payer health care system.

New-onset Obesity After Lung Transplantation: Incidence, Risk Factors, and Clinical Outcomes.

BACKGROUND: Lung transplant (LTx) recipients who gain weight after transplantation may experience an upward shift in body mass index (BMI) that places them in the obese category. The incidence, risk factors, and impact on metabolic health and mortality of new-onset obesity have not been documented in the LTx setting. METHODS: This single-center retrospective study included 564 LTx recipients. Individuals were stratified according to their BMI trajectories from pretransplant evaluation up to 10 y posttransplant. New-onset obesity was defined as a pretransplant BMI <30 kg/m 2 and posttransplant BMI >30 kg/m 2 . The incidence, risk factors, and posttransplant diabetes mellitus, metabolic syndrome, and mortality of recipients with new-onset obesity were compared with those of nonobese (BMI <30 kg/m 2 , pre/post-LTx), consistently obese (BMI >30 kg/m 2 , pre/post-LTx), and obese recipients with weight loss (BMI >30 kg/m 2 pre-LTx, BMI <30 kg/m 2 post-LTx). RESULTS: We found that 14% of recipients developed obesity after transplantation. Overweight individuals (odds ratio [OR]: 9.01; 95% confidence interval [CI] [4.86-16.69]; P < 0.001) and candidates with chronic obstructive pulmonary disease (OR: 6.93; 95% CI [2.30-20.85]; P = 0.001) and other diagnoses (OR: 4.28; 95% CI [1.22-14.98]; P = 0.023) were at greater risk. Multivariable regression analysis showed that new-onset obesity was associated with a greater risk of metabolic syndrome (hazard ratio: 1.70; 95% CI [1.17-2.46]; P = 0.005), but not of posttransplant diabetes mellitus, than nonobesity. Recipients with new-onset obesity had a survival comparable to that of consistently obese individuals. CONCLUSIONS: A greater understanding of the multifaceted nature of post-LTx obesity may lead to interventions that are better tailored to the characteristics of these individuals.