Robotic Lobectomy Is Cost-effective and Provides Comparable Health Utility Scores to Video-assisted Lobectomy: Early Results of the RAVAL Trial.

OBJECTIVE: The aim of this study was to determine if robotic-assisted lobectomy (RPL-4) is cost-effective and offers improved patient-reported health utility for patients with early-stage non-small cell lung cancer when compared with video-assisted thoracic surgery lobectomy (VATS-lobectomy). BACKGROUND: Barriers against the adoption of RPL-4 in publicly funded health care include the paucity of high-quality prospective trials and the perceived high cost of robotic surgery. METHODS: Patients were enrolled in a blinded, multicentered, randomized controlled trial in Canada, the United States, and France, and were randomized 1:1 to either RPL-4 or VATS-lobectomy. EuroQol 5 Dimension 5 Level (EQ-5D-5L) was administered at baseline and postoperative day 1; weeks 3, 7, 12; and months 6 and 12. Direct and indirect costs were tracked using standard methods. Seemingly Unrelated Regression was applied to estimate the cost effect, adjusting for baseline health utility. The incremental cost-effectiveness ratio was generated by 10,000 bootstrap samples with multivariate imputation by chained equations. RESULTS: Of 406 patients screened, 186 were randomized, and 164 analyzed after the final eligibility review (RPL-4: n=81; VATS-lobectomy: n=83). Twelve-month follow-up was completed by 94.51% (155/164) of participants. The median age was 68 (60-74). There were no significant differences in body mass index, comorbidity, pulmonary function, smoking status, baseline health utility, or tumor characteristics between arms. The mean 12-week health utility score was 0.85 (0.10) for RPL-4 and 0.80 (0.19) for VATS-lobectomy ( P =0.02). Significantly more lymph nodes were sampled [10 (8-13) vs 8 (5-10); P =0.003] in the RPL-4 arm. The incremental cost/quality-adjusted life year of RPL-4 was $14,925.62 (95% CI: $6843.69, $23,007.56) at 12 months. CONCLUSION: Early results of the RAVAL trial suggest that RPL-4 is cost-effective and associated with comparable short-term patient-reported health utility scores when compared with VATS-lobectomy.

Outcomes of lung transplantation from organ donation after medical assistance in dying: First North American experience.

Over 2.5% of deaths in Canada occur as a result from medical assisting in dying (MAID), and a subset of these deaths result in organ donation. However, detailed outcomes of lung transplant recipients using these donors is lacking. This is a retrospective single center cohort study comparing lung transplantation outcomes after donation using MAID donors compared to neurologically determined death and controlled donation after circulatory death (NDD/cDCD) donors from February 2018 to July 2021. Thirty-three patients received lungs from MAID donors, and 560 patients received lungs from NDD/cDCD donors. The donor diagnoses leading to MAID provision were degenerative neurological diseases (n = 33) and end stage organ failure (n = 5). MAID donors were significantly older than NDD/cDCD donors (56 [IQR 49-64] years vs. 48 [32-59]; p = .0009). Median ventilation period and 30 day mortality were not significantly different between MAID and NDD/cDCD lungs recipients (ventilation: 1 day [1-3] vs 2 days [1-3]; p = .37, deaths 0% [0/33] vs. 2% [11/560], p = .99 respectively). Intermediate-term outcomes were also similar. In summary, for lung transplantation using donors after MAID, recipient outcomes were excellent. Therefore, where this practice is permitted, donation after MAID should be strongly considered for lung transplantation as a way to respect donor wishes while substantially improving outcomes for recipients with end-stage lung disease.

Vessel network extraction and analysis of mouse pulmonary vasculature via X-ray micro-computed tomographic imaging.

In this work, non-invasive high-spatial resolution three-dimensional (3D) X-ray micro-computed tomography (µCT) of healthy mouse lung vasculature is performed. Methodologies are presented for filtering, segmenting, and skeletonizing the collected 3D images. Novel methods for the removal of spurious branch artefacts from the skeletonized 3D image are introduced, and these novel methods involve a combination of distance transform gradients, diameter-length ratios, and the fast marching method (FMM). These new techniques of spurious branch removal result in the consistent removal of spurious branches without compromising the connectivity of the pulmonary circuit. Analysis of the filtered, skeletonized, and segmented 3D images is performed using a newly developed Vessel Network Extraction algorithm to fully characterize the morphology of the mouse pulmonary circuit. The removal of spurious branches from the skeletonized image results in an accurate representation of the pulmonary circuit with significantly less variability in vessel diameter and vessel length in each generation. The branching morphology of a full pulmonary circuit is characterized by the mean diameter per generation and number of vessels per generation. The methods presented in this paper lead to a significant improvement in the characterization of 3D vasculature imaging, allow for automatic separation of arteries and veins, and for the characterization of generations containing capillaries and intrapulmonary arteriovenous anastomoses (IPAVA).

A method for translational rat ex vivo lung perfusion experimentation.

The application of ex vivo lung perfusion (EVLP) has significantly increased the successful clinical use of marginal donor lungs. While large animal EVLP models exist to test new strategies to improve organ repair, there is currently no rat EVLP model capable of maintaining long-term lung viability. Here, we describe a new rat EVLP model that addresses this need, while enabling the study of lung injury due to cold ischemic time (CIT). The technique involves perfusing and ventilating male Lewis rat donor lungs for 4 h before transplanting the left lung into a recipient rat and then evaluating lung function 2 h after reperfusion. To test injury within this model, lungs were divided into groups and exposed to different CITs (i.e., 20 min, 6 h, 12 h, 18 h and 24 h). Experiments involving the 24-h-CIT group were prematurely terminated due to the development of severe edema. For the other groups, no differences in the ratio of arterial oxygen partial pressure to fractional inspired oxygen ([Formula: see text]/[Formula: see text]) were observed during EVLP; however, lung compliance decreased over time in the 18-h group (P = 0.012) and the [Formula: see text]/[Formula: see text] of the blood from the left pulmonary vein 2 h after transplantation was lower compared with 20-min-CIT group (P = 0.0062). This new model maintained stable lung function during 4-h EVLP and after transplantation when exposed to up to 12 h of CIT.

Initial lung transplantation experience with uncontrolled donation after cardiac death in North America.

Uncontrolled donation after cardiac death (uDCD) has the potential to ameliorate the shortage of suitable lungs for transplant. To date, no lung transplant data from these donors are available from North America. We describe the successful use of these donors using a simple method of in situ lung inflation so that the organ can be protected from warm ischemic injury. Forty-four potential donors were approached, and family consent was obtained in 30 cases (68%). Of these, the lung transplant team evaluated 16 uDCDs on site, and 14 were considered for transplant pending ex vivo lung perfusion assessment. Five lungs were ultimately used for transplant (16.7% use rate from consented donors). The mean warm ischemic time was 2.8 hours. No primary graft dysfunction grade 3 was observed at 24, 48, or 72 hours after transplant. Median intensive care unit stay was 5 days (range: 2-78 days), and median hospital stay was 17 days (range: 8-100 days). The 30-day mortality was 0%. Four of 5 patients are alive at a median of 651 days (range: 121-1254 days) with preserved lung function. This study demonstrates the proof of concept and the potential for uDCD lung donation using a simple donor intervention.

MRI method for labeling and imaging decellularized extracellular matrix scaffolds for tissue engineering.

PURPOSE: To develop a facile method for labeling and imaging decellularized extracellular matrix (dECM) scaffolds intended for regenerating 3D tissues. METHODS: A small molecule manganese porphyrin, MnPNH2 , was synthesized and used to label dECM scaffolds made from porcine bladder and trachea and murine whole lungs. The labeling protocol was optimized on bladder dECM, and imaging on a 3T clinical scanner was performed to assess reductions in T1 and T2 relaxation times. In vivo MRI was performed on dECM injected in the rat dorsum to verify sensitivity of detection. Toxicity assays for cell viability, metabolism, and proliferation were performed on human umbilical vein endothelial cells. The incorporation of MnPNH2 and its long-term retention in dECM were assessed on transmission electron microscopy and ultraviolet absorbance of eluted MnPNH2 over time. RESULTS: All tissues, including thick whole 3D organs, were uniformly labeled and demonstrated high signal-to-noise on MRI. A nearly 10-fold reduction in T1 was consistently obtained at a labeling dose of 0.4 mM, and even 0.2 mM provided sufficient contrast in vivo and ex vivo. No toxicity was observed up to 0.4 mM, the maximum tested. Binding studies suggested nonspecific association, and retention studies in the labeled whole decellularized lungs revealed less than 20% MnPNH2 loss over 30 days, the majority occurring in the first 3 days after labeling. CONCLUSION: The proposed labeling method is the first report for visualizing dECM on MRI and has the potential for long-term monitoring and optimization of dECM-based organ tissue engineering.

Cell-Based Therapeutic Approaches for Cystic Fibrosis.

Cystic Fibrosis (CF) is a chronic autosomal recessive disease caused by defects in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic Fibrosis affects multiple organs but progressive remodeling of the airways, mucus accumulation, and chronic inflammation in the lung, result in lung disease as the major cause of morbidity and mortality. While advances in management of CF symptoms have increased the life expectancy of this devastating disease, and there is tremendous excitement about the potential of new agents targeting the CFTR molecule itself, there is still no curative treatment. With the recent advances in the identification of endogenous airway progenitor cells and in directed differentiation of pluripotent cell sources, cell-based therapeutic approaches for CF have become a plausible treatment method with the potential to ultimately cure the disease. In this review, we highlight the current state of cell therapy in the CF field focusing on the relevant autologous and allogeneic cell populations under investigation and the challenges associated with their use. In addition, we present advances in induced pluripotent stem (iPS) cell approaches and emerging new genetic engineering methods, which have the capacity to overcome the current limitations hindering cell therapy approaches.

Donor prone positioning protects lungs from injury during warm ischemia.

A large proportion of controlled donation after circulatory death (cDCD) donor lungs are declined because cardiac arrest does not occur within a suitable time after the withdrawal of life-sustaining therapy. Improved strategies to preserve lungs after asystole may allow the recovery team to arrive after death actually occurs and enable the recovery of lungs from more cDCD donors. The aim of this study was to determine the effect of donor positioning on the quality of lung preservation after cardiac arrest in a cDCD model. Cardiac arrest was induced by withdrawal of ventilation under anesthesia in pigs. After asystole, animals were divided into 2 groups based on body positioning (supine or prone). All animals were subjected to 3 hours of warm ischemia. After the observation period, donor lungs were explanted and preserved at 4°C for 6 hours, followed by 6 hours of physiologic and biological lung assessment under normothermic ex vivo lung perfusion. Donor lungs from the prone group displayed significantly greater quality as reflected by better function during ex vivo lung perfusion, less edema formation, less cell death, and decreased inflammation compared with the supine group. A simple maneuver of donor prone positioning after cardiac arrest significantly improves lung graft preservation and function.

Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2.

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vß chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).

CT-guided Microcoil Pulmonary Nodule Localization prior to Video-assisted Thoracoscopic Surgery: Diagnostic Utility and Recurrence-Free Survival.

Background CT-guided microcoil localization has been shown to reduce the need for thoracotomy or video-assisted thoracoscopic surgery (VATS) anatomic resection. However, only short-term follow-up after CT-guided microcoil localization and lung resection has been previously reported. Purpose To assess the diagnostic utility and recurrence-free survival over a minimum of 2 years following CT-guided microcoil localization and VATS. Materials and Methods Among 1950 VATS procedures performed in a single tertiary institution from October 2008 through April 2016, 124 consecutive patients with CT-guided microcoil localization were retrospectively evaluated. Patient demographics, nodule characteristics, and histopathologic findings were recorded. The primary end point was recurrence-free survival after 2 or more years of CT surveillance. Statistical analysis included Kaplan-Meier survival curves and Cox regression. Results In 124 patients (men, 35%; mean age, 65 years ± 12) with a nodule found at CT, microcoil localization and VATS resection were performed for a total of 126 nodules (mean size, 13 mm ± 6; mean distance to pleura, 20 mm ± 9). On presurgical CT evaluation, 42% (53 of 126) of nodules were solid, 33% (41 of 126) were ground glass, and 24% (30 of 126) were subsolid. VATS excisional biopsy altered cytopathologic diagnosis in 21% (five of 24) of patients with prior diagnostic premicrocoil CT-guided biopsy. At histopathologic examination, 17% (21 of 126) of the nodules were adenocarcinoma in situ, 17% (22 of 126) were minimally invasive adenocarcinoma, 30% (38 of 126) were invasive lung primary tumors, and 22% (28 of 126) were metastases. Among the 72 patients with malignancy at histopathologic examination and at least 2 years of CT surveillance, local recurrence occurred in 7% (five of 72), intrathoracic recurrence in 22% (16 of 72), and extrathoracic recurrence in 18% (13 of 72) after 2 or more years of CT surveillance. There was no recurrence for adenocarcinoma in situ, minimally invasive adenocarcinoma, or invasive lung tumors measuring less than 1 cm. After multivariable adjustment, nodule location at a distance greater than 10 mm from the pleura was an independent predictor of time to recurrence (hazard ratio, 2.9 [95% confidence interval: 1.1, 7.4]; P = .03). Conclusion CT-guided microcoil localization and video-assisted thoracoscopic surgical resection alter clinical management and were associated with excellent recurrence-free survival for superficial premalignant, minimally invasive, and small invasive lung tumors. © RSNA, 2019 Online supplemental material is available for this article.

SOX2 and PI3K Cooperate to Induce and Stabilize a Squamous-Committed Stem Cell Injury State during Lung Squamous Cell Carcinoma Pathogenesis.

Although cancers are considered stem cell diseases, mechanisms involving stem cell alterations are poorly understood. Squamous cell carcinoma (SQCC) is the second most common lung cancer, and its pathogenesis appears to hinge on changes in the stem cell behavior of basal cells in the bronchial airways. Basal cells are normally quiescent and differentiate into mucociliary epithelia. Smoking triggers a hyperproliferative response resulting in progressive premalignant epithelial changes ranging from squamous metaplasia to dysplasia. These changes can regress naturally, even with chronic smoking. However, for unknown reasons, dysplasias have higher progression rates than earlier stages. We used primary human tracheobronchial basal cells to investigate how copy number gains in SOX2 and PIK3CA at 3q26-28, which co-occur in dysplasia and are observed in 94% of SQCCs, may promote progression. We find that SOX2 cooperates with PI3K signaling, which is activated by smoking, to initiate the squamous injury response in basal cells. This response involves SOX9 repression, and, accordingly, SOX2 and PI3K signaling levels are high during dysplasia, while SOX9 is not expressed. By contrast, during regeneration of mucociliary epithelia, PI3K signaling is low and basal cells transiently enter a SOX2LoSOX9Hi state, with SOX9 promoting proliferation and preventing squamous differentiation. Transient reduction in SOX2 is necessary for ciliogenesis, although SOX2 expression later rises and drives mucinous differentiation, as SOX9 levels decline. Frequent coamplification of SOX2 and PIK3CA in dysplasia may, thus, promote progression by locking basal cells in a SOX2HiSOX9Lo state with active PI3K signaling, which sustains the squamous injury response while precluding normal mucociliary differentiation. Surprisingly, we find that, although later in invasive carcinoma SOX9 is generally expressed at low levels, its expression is higher in a subset of SQCCs with less squamous identity and worse clinical outcome. We propose that early pathogenesis of most SQCCs involves stabilization of the squamous injury state in stem cells through copy number gains at 3q, with the pro-proliferative activity of SOX9 possibly being exploited in a subset of SQCCs in later stages.

Frailty assessment prior to thoracic surgery for lung or esophageal cancer: a feasibility study.

BACKGROUND: Frailty assessment has not been thoroughly assessed in thoracic surgery. Our primary objective was to assess the feasibility of comprehensive frailty testing prior to lung and esophageal surgery for cancer. The secondary objective was to assess the utility of frailty indices in risk assessment prior to thoracic surgery. METHODS: Prospectively recruited patients completed multiple physiotherapy tests (6-min walk, gait speed, hand-grip strength), risk stratification (Charlson Comorbidity Index, Revised Cardiac Risk Index, Modified Frailty Index), and quality of life questionnaires. Lean psoas area was also assessed by a radiologist using positron emission tomography/computed tomography scans. Data was analyzed using Fisher's exact, Mann-Whitney U and independent t tests. RESULTS: The feasibility of comprehensive frailty assessment was assessed over a 4-month period among 40 patients (esophagus n = 20; lung n = 20). Risk stratification questionnaires administered in clinic had 100% completion rates. Physiotherapy testing required a trained physiotherapist and an additional visit to the pre-admission clinic; these tests proved difficult to coordinate and had lower completion rates (63-75%). Although most measures were not significantly associated with occurrence of complications, the Modified Frailty Index approached statistical significance (p = 0.06). CONCLUSIONS: Frailty assessment is feasible in the pre-operative outpatient setting and had a high degree of acceptance among surgeons and patients. Of the risk stratification questionnaires, the Modified Frailty Index may be useful in predicting outcomes as per this feasibility study. Pre-operative frailty assessment can identify vulnerable oncology patients to aid in treatment planning with the goal of optimizing clinical outcomes and resource allocation.

Towards donor lung recovery-gene expression changes during ex vivo lung perfusion of human lungs.

We and others have demonstrated that acellular normothermic ex vivo lung perfusion of high-risk donor lungs can result in posttransplant outcomes equivalent to that of contemporaneous lung transplantation using standard donor lungs. However, the mechanism of this effect remains unclear. Given the restoration of cellular metabolic activity during normothermic perfusion, one possibility is that of lung healing via natural innate recovery mechanisms. We explored this by examining the gene expression changes occurring in human lungs during ex vivo lung perfusion. Human lungs clinically rejected for transplantation were perfused for 12 hours of EVLP with biopsies taken at the start, at 1 hour, at 3 hours, and then every 3 hours thereafter to 12 hours. Temporal changes were identified in 2585 genes using the Short Time-series Expression Miner and used for pathway analysis. Despite increases in endothelial markers of inflammation, circulating leukocyte cell-specific gene expression fell over 12 hours of ex vivo lung perfusion (EVLP), suggesting an interrupted inflammation response secondary to washout of circulating leukocytes. Analysis of these gene changes suggests lung recovery follows specific stages: cellular death, cellular preservation, cellular reorganization, and cellular invasion. EVLP may improve posttransplant lung function by washout of leukocytes and facilitating innate mechanisms of repair.

Partial Restoration of CFTR Function in cftr-Null Mice following Targeted Cell Replacement Therapy.

Cystic fibrosis (CF) is a fatal recessive genetic disorder caused by a mutation in the gene encoding CF transmembrane conductance regulator (CFTR) protein. Alteration in CFTR leads to thick airway mucus and bacterial infection. Cell therapy has been proposed for CFTR restoration, but efficacy has been limited by low engraftment levels. In our previous studies, we have shown that using a pre-conditioning regimen in combination with optimization of cell number and time of delivery, we could obtain greater bone marrow cell (BMC) retention in the lung. Here, we found that optimized delivery of wild-type (WT) BMC contributed to apical CFTR expression in airway epithelium and restoration of select ceramide species and fatty acids in CFTR-/- mice. Importantly, WT BMC delivery delayed Pseudomonas aeruginosa lung infection and increased survival of CFTR-/- recipients. Only WT BMCs had a beneficial effect beyond 6 months, suggesting a dual mechanism of BMC benefit: a non-specific effect early after cell delivery, possibly due to the recruitment of macrophages and neutrophils, and a late beneficial effect dependent on long-term CFTR expression. Taken together, our results suggest that BMC can improve overall lung function and may have potential therapeutic benefit for the treatment of CF.

Skin-derived precursors from human subjects with Type 2 diabetes yield dysfunctional vascular smooth muscle cells.

Objective: Few methods enable molecular and cellular studies of vascular aging or Type 2 diabetes (T2D). Here, we report a new approach to studying human vascular smooth muscle cell (VSMC) pathophysiology by examining VSMCs differentiated from progenitors found in skin. Approach and results: Skin-derived precursors (SKPs) were cultured from biopsies (N=164, ∼1 cm2) taken from the edges of surgical incisions of older adults (N=158; males 72%; mean age 62.7 ± 13 years) undergoing cardiothoracic surgery, and differentiated into VSMCs at high efficiency (>80% yield). The number of SKPs isolated from subjects with T2D was ∼50% lower than those without T2D (cells/g: 0.18 ± 0.03, N=58 versus 0.40 ± 0.05, N=100, P<0.05). Importantly, SKP-derived VSMCs from subjects with T2D had higher Fluo-5F-determined baseline cytosolic Ca2+ concentrations (AU: 1,968 ± 160, N=7 versus 1,386 ± 170, N=13, P<0.05), and a trend toward greater Ca2+ cycling responses to norepinephrine (NE) (AUC: 177,207 ± 24,669, N=7 versus 101,537 ± 15,881, N=20, P<0.08) despite a reduced frequency of Ca2+ cycling (events s-1 cell-1: 0.011 ± 0.004, N=8 versus 0.021 ± 0.003, N=19, P<0.05) than those without T2D. SKP-derived VSMCs from subjects with T2D also manifest enhanced sensitivity to phenylephrine (PE) in an impedance-based assay (EC50 nM: 72.3 ± 63.6, N=5 versus 3,684 ± 3,122, N=9, P<0.05), and impaired wound closure in vitro (% closure: 21.9 ± 3.6, N=4 versus 67.0 ± 10.3, N=4, P<0.05). Compared with aortic- and saphenous vein-derived primary VSMCs, SKP-derived VSMCs are functionally distinct, but mirror defects of T2D also exhibited by primary VSMCs. CONCLUSION: Skin biopsies from older adults yield sufficient SKPs to differentiate VSMCs, which reveal abnormal phenotypes of T2D that survive differentiation and persist even after long-term normoglycemic culture.

Circulating Cell Death Biomarkers May Predict Survival in Human Lung Transplantation.

RATIONALE: Immediate graft performance after lung transplantation is associated with short- and long-term clinical outcomes. However, the biologic mechanism that determines outcomes is not fully understood. OBJECTIVES: To investigate the impact of cell death signals at 24 and 48 hours after lung transplantation on short- and long-term clinical outcomes. METHODS: Plasma samples were collected pretransplantation and at 24 and 48 hours after transplant from 60 bilateral lung transplant recipients. Ten patients had primary graft dysfunction (PGD) grade 3 (PaO2/FiO2 ratio <200 or on extracorporeal membrane oxygenation support) at 72 hours after transplant (PGD group). The remaining 50 patients were defined as the control group. Levels of plasma M30 (signifying epithelial apoptosis), M65 (signifying epithelial apoptosis plus necrosis), and high-mobility group box 1 protein (HMGB-1; signifying necrosis of all cell types) were measured by ELISA and correlated with clinical outcomes. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. Prediction accuracy of markers was assessed by calculated area under the curve of receiver operating characteristic graph. MEASUREMENTS AND MAIN RESULTS: The PGD group had significantly higher M30 and M65 levels at 24 and 48 hours after transplant compared with the control group. There was no significant difference in HMGB-1. Area under the curve for 1-year survival was 0.86, 0.93, and 0.51 for M30, M65, and HMGB-1 at 48 hours, respectively. Survival analysis showed that higher M30 and M65 levels at 24 and 48 hours were significantly associated with worse survival. M65 at 48 hours remained significant even after adjustment for PGD. HMGB-1 was not significantly associated with survival. CONCLUSIONS: Recipient plasma concentration of epithelial cell death markers (M30, M65) after lung transplantation is negatively correlated with early graft performance and long-term survival.

Robotic-assisted thoracoscopic surgery for lung resection: the first Canadian series.

BACKGROUND: Robotic surgery was introduced as a platform for minimally invasive lung resection in Canada in October 2011. We present the first Canadian series of robotic pulmonary resection for lung cancer. METHODS: Prospective databases at 2 institutions were queried for patients who underwent robotic resection for lung cancer between October 2011 and June 2015. To examine the effect of learning curves on patient and process outcomes, data were organized into 3 temporal tertiles, stratified by surgeon. RESULTS: A total of 167 consecutive patients were included in the study. Median age was 66 (range 27-88) years, and 46.1% (n = 77) of patients were men. The majority of patients (n = 141, 84%) underwent robotic lobectomy. Median duration of surgery was 270 (interquartile range [IQR] 233-326) minutes, and median length of stay (LOS) was 4 (IQR 3-6) days. Twelve patients (7%) were converted to thoracotomy. Total duration of surgery and console time decreased significantly (p < 0.001) across tertiles, with a steady decline until case 20, followed by a plateau effect. Across tertiles, there was no significant difference in LOS, number of lymph node stations removed, or perioperative complications. CONCLUSION: The results of this case series are comparable to those reported in the literature. A prospective study to examine the outcomes and cost of robotic pulmonary resection compared with video-assisted thoracoscopic surgery should be done in the context of the Canadian health care system. We have presented the first consecutive case series of robotic lobectomy in Canada. Outcomes compare favourably to other series in the literature.

CONTEXTE: C'est en octobre 2011 que la chirurgie robotisée a fait son entrée au Canada comme approche à la résection pulmonaire minimalement effractive. Nous présentons à notre connaissance la première série canadienne sur la résection pulmonaire robotisée pour le cancer du poumon. MÉTHODES: Nous avons interrogé les bases de données prospectives de 2 établissements pour recenser les patients ayant subi une résection robotisée pour un cancer du poumon entre octobre 2011 et juin 2015. Nous avons organisé les données en 3 tertiles temporels et nous les avons stratifiées par chirurgien pour mesurer l'effet des courbes d'apprentissage sur les résultats enregistrés chez les patients et du point de vue des procédés. RÉSULTATS: En tout, 167 patients consécutifs ont été inclus dans l'étude. L'âge médian était de 66 ans (entre 27 et 88 ans) et 46,1 % (n = 77) étaient des hommes. La majorité des patients (n = 141, 84 %) ont subi une lobectomie robotisée. La durée moyenne des interventions a été de 270 minutes (intervalle interquartile [IIQ] 96) et la durée médiane des séjours a été de 4 jours (IIQ 3). L'intervention s'est transformée en thoracotomie chez 12 patients (7 %). La durée totale de la chirurgie et le temps passé à la console ont diminué significativement (p < 0,001) selon les différents tertiles, avec un déclin constant jusqu'au cas no 20, suivi d'un effet de plateau. Entre les tertiles, on n'a noté aucune différence significative pour ce qui est de la durée des séjours hospitaliers, du nombre de chaînes ganglionnaires excisées ou des complications périopératoires. CONCLUSION: Les résultats de cette série de cas sont comparables à ceux qui sont rapportés dans la documentation. Une étude prospective, dans le but de comparer les résultats et le coût des résections pulmonaires robotisées à ceux des chirurgies thoracoscopiques vidéo-assistées, s'imposerait dans le contexte des soins de santé canadiens. Nous avons présenté la première série de cas consécutifs de lobectomies robotisées au Canada. Les résultats se comparent favorablement à ceux d'autres séries décrites dans la documentation.

Depletion of bone marrow CCSP-expressing cells delays airway regeneration.

The contribution of bone marrow cells (BMC) in lung repair is controversial. We previously reported a subpopulation of BMC that express Clara cell secretory protein (CCSP). To determine the contribution of endogenous CCSP(+) BMC to airway regeneration, we performed bone marrow transplantation studies using the CCtk mouse, which expresses a thymidine kinase suicide gene under regulation of the CCSP promoter. Mice were transplanted with wild-type or CCtk BMC and treated with ganciclovir to eliminate CCSP(+) cells. After airway injury using naphthalene, mice depleted of CCSP(+) BMC had more inflammatory cells in lung and decreased levels of oxygen in arterial blood. They also had reduced expression of airway epithelial genes and less Clara cells compared to control mice that had intact CCSP(+) BMC and bone marrow derived CCSP(+) cells in the airways. After naphthalene injury, administration of CCSP reproduced the beneficial effect of CCSP(+) BMC by improving recovery of airway epithelium, reducing lung inflammation and increasing oxygen in arterial blood from mice depleted of CCSP(+) BMC. Our data demonstrate that ablation of CCSP(+) BMC delays airway recovery and suggests the beneficial effect of CCSP(+) BMC in lung recovery is in part due to production of CCSP itself.

Effects of Recipient Age and Diagnosis on Health-related Quality-of-Life Benefit of Lung Transplantation.

RATIONALE: The average age of lung transplant recipients is increasing, and the mix of recipient indications for transplantation is changing. OBJECTIVES: To determine whether the health-related quality-of-life (HRQL) benefit of lung transplantation differs by recipient age and diagnosis. METHODS: In this prospective cohort study, we obtained serial HRQL measurements in adults with advanced lung disease who subsequently underwent lung transplantation (2004-2012). HRQL assessments included the St. George's Respiratory Questionnaire, 36-Item Short-Form Health Survey (SF-36), EQ-5D, Standard Gamble, and Visual Analog Scale for current health. We used linear mixed effects models for associations between age or diagnosis and changes in HRQL with transplantation. To address potential survivorship bias, we fitted Markov models to the distribution of discrete post-transplant health states (HRQL better than pretransplant, not better, or dead) and estimated quality-adjusted life-years post-transplant. MEASUREMENTS AND MAIN RESULTS: A total of 430 subjects were listed, 387 were transplanted, and 326 provided both pretransplant and post-transplant data. Transplantation conferred large improvements in all HRQL measures: St. George's change of -47 units (95% confidence interval, -48 to -44), 36-Item Short-Form Health Survey physical component summary score of 17.7 (16.5-18.9), EQ-5D of 0.27 (0.24-0.30), Standard Gamble of 0.48 (0.44-0.51), and Visual Analog of 44 (42-47). Age was not associated with meaningful differences in the HRQL benefits of transplantation. There was less HRQL benefit in interstitial lung disease than in cystic fibrosis. CONCLUSIONS: Lung transplantation confers large HRQL benefits, which vary by recipient diagnosis, but do not differ substantially in older recipients.

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF.

The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.