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Objective On November 24, 2017, Organ Procurement and Transplantation Network implemented a change to lung allocation replacing donor service area with a 250 nautical mile radius around donor hospitals. We sought to evaluate the experience of a small to medium size center following implementation. Methods Patients (47 pre and 54 post) undergoing lung transplantation were identified from institutional database from January 2016 to October 2019. Detailed chart review and analysis of institutional cost data was performed. Univariate analysis was performed to compare eras. Results Similar short-term mortality and primary graft dysfunction were observed between groups. Decreased local donation (68% vs 6%, p < 0.001), increased travel distance (145 vs 235 miles, p = 0.004), travel cost ($8,626 vs $14,482, p < 0.001), and total procurement cost ($60,852 vs. $69,052, p = 0.001) were observed post implementation. We also document an increase in waitlist mortality post-implementation (6.9 vs 31.6 per 100 patient years, p < 0.001). Conclusions Following implementation of the new allocation policy in a small to medium size center, several changes were in accordance with policy intention. However, concerning shifts emerged including increased waitlist mortality and resource utilization. Continued close monitoring of transplant centers stratified by size and location are paramount to maintaining global availability of lung transplantation to all Americans regardless of geographic residence or socioeconomic status. (Word Count: 219/250)

Objective National Institutes of Health (NIH) funding for academic (noncardiac) thoracic surgeons at the top-140 NIH-funded institutes in the United States was assessed. We hypothesized that thoracic surgeons have difficulty in obtaining NIH funding in a difficult funding climate. Methods The top-140 NIH-funded institutes' faculty pages were searched for noncardiac thoracic surgeons. Surgeon data, including gender, academic rank, and postfellowship training were recorded. These surgeons were then queried in NIH Research Portfolio Online Reporting Tools Expenditures and Results for their funding history. Analysis of the resulting grants (1980-2019) included grant type, funding amount, project start/end dates, publications, and a citation-based Grant Impact Metric to evaluate productivity. Results A total of 395 general thoracic surgeons were evaluated with 63 (16%) receiving NIH funding. These 63 surgeons received 136 grants totaling $228 million, resulting in 1772 publications, and generating more than 50,000 citations. Thoracic surgeons have obtained NIH funding at an increasing rate (1980-2019); however, they have a low percentage of R01 renewal (17.3%). NIH-funded thoracic surgeons were more likely to have a higher professorship level. Thoracic surgeons perform similarly to other physician-scientists in converting K-Awards into R01 funding. Conclusions Contrary to our hypothesis, thoracic surgeons have received more NIH funding over time. Thoracic surgeons are able to fill the roles of modern surgeon-scientists by obtaining NIH funding during an era of increasing clinical demands. The NIH should continue to support this mission.

Objective The current supply of acceptable donor lungs is not sufficient for the number of patients awaiting transplantation. We hypothesized that ex vivo lung perfusion (EVLP) with targeted drug therapy would allow successful rehabilitation and transplantation of donation after circulatory death lungs exposed to 2 hours of warm ischemia. Methods Donor porcine lungs were procured after 2 hours of warm ischemia postcardiac arrest and subjected to 4 hours of cold preservation or EVLP. ATL802, an adenosine A 2B receptor antagonist, was administered to select groups. Four groups (n = 4/group) were randomized: cold preservation (Cold), cold preservation with ATL802 during reperfusion (Cold + ATL802), EVLP (EVLP), and EVLP with ATL802 during ex vivo perfusion (EVLP + ATL802). Lungs subsequently were transplanted, reperfused, and assessed by measuring dynamic lung compliance and oxygenation capacity. Results EVLP + ATL802 significantly improved dynamic lung compliance compared with EVLP (25.0 ± 1.8 vs 17.0 ± 2.4 mL/cmH 2 O, P = .04), and compared with cold preservation (Cold: 12.2 ± 1.3, P = .004; Cold + ATL802: 10.6 ± 2.0 mL/cmH 2 O, P = .002). Oxygenation capacity was highest in EVLP (440.4 ± 37.0 vs Cold: 174.0 ± 61.3 mm Hg, P = .037). No differences in oxygenation or pulmonary edema were observed between EVLP and EVLP + ATL802. A significant decrease in interleukin-12 expression in tissue and bronchoalveolar lavage was identified between groups EVLP and EVLP + ATL802, along with less neutrophil infiltration. Conclusions Severely injured donation after circulatory death lungs subjected to 2 hours of warm ischemia are transplanted successfully after enhanced EVLP with targeted drug therapy. Increased use of lungs after uncontrolled donor cardiac death and prolonged warm ischemia may be possible and may improve transplant wait list times and mortality.

Objective Critical organ shortages have resulted in ex vivo lung perfusion gaining clinical acceptance for lung evaluation and rehabilitation to expand the use of donation after circulatory death organs for lung transplantation. We hypothesized that an innovative use of airway pressure release ventilation during ex vivo lung perfusion improves lung function after transplantation. Methods Two groups (n = 4 animals/group) of porcine donation after circulatory death donor lungs were procured after hypoxic cardiac arrest and a 2-hour period of warm ischemia, followed by a 4-hour period of ex vivo lung perfusion rehabilitation with standard conventional volume-based ventilation or pressure-based airway pressure release ventilation. Left lungs were subsequently transplanted into recipient animals and reperfused for 4 hours. Blood gases for partial pressure of oxygen/inspired oxygen fraction ratios, airway pressures for calculation of compliance, and percent wet weight gain during ex vivo lung perfusion and reperfusion were measured. Results Airway pressure release ventilation during ex vivo lung perfusion significantly improved left lung oxygenation at 2 hours (561.5 ± 83.9 mm Hg vs 341.1 ± 136.1 mm Hg) and 4 hours (569.1 ± 18.3 mm Hg vs 463.5 ± 78.4 mm Hg). Likewise, compliance was significantly higher at 2 hours (26.0 ± 5.2 mL/cm H 2 O vs 15.0 ± 4.6 mL/cm H 2 O) and 4 hours (30.6 ± 1.3 mL/cm H 2 O vs 17.7 ± 5.9 mL/cm H 2 O) after transplantation. Finally, airway pressure release ventilation significantly reduced lung edema development on ex vivo lung perfusion on the basis of percentage of weight gain (36.9% ± 14.6% vs 73.9% ± 4.9%). There was no difference in additional edema accumulation 4 hours after reperfusion. Conclusions Pressure-directed airway pressure release ventilation strategy during ex vivo lung perfusion improves the rehabilitation of severely injured donation after circulatory death lungs. After transplant, these lungs demonstrate superior lung-specific oxygenation and dynamic compliance compared with lungs ventilated with standard conventional ventilation. This strategy, if implemented into clinical ex vivo lung perfusion protocols, could advance the field of donation after circulatory death lung rehabilitation to expand the lung donor pool.

Video-assisted thoracoscopic surgery lobectomy has been associated with improved pain, length of stay, and outcomes compared with open lobectomy. However, enhanced recovery protocols improve outcomes after both procedures. We aimed to compare video-assisted thoracoscopic surgery and open lobectomy in the setting of a comprehensive enhanced recovery protocol.All patients undergoing lobectomy for lung cancer at a single institution since the adoption of an enhanced recovery protocol (May 2016 to December 2018) were stratified by video-assisted thoracoscopic surgery versus open status and compared. Demographics and outcomes, including length of stay, daily pain scores, and short-term operative complications, were compared using standard univariate statistics and multivariable models.A total of 130 patients underwent lobectomy, including 71 (54.6%) undergoing video-assisted thoracoscopic surgery and 59 (45.4%) undergoing open surgery. Video-assisted thoracoscopic surgery versus open cases exhibited similar length of stay (median 4 days for both, P = .07), opioid requirement (33.2 vs 30.8 mg morphine equivalents, P = .86), and pain scores at 0, 1, 2, and 3 days after surgery (4.3 vs 2.8, P = .12; 4.4 vs 3.7, P = .27; 3.9 vs 3.5, P = .83; and 3.4 vs 3.5, P = .98, respectively). Patients undergoing video-assisted thoracoscopic surgery lobectomy exhibited lower rates of readmission (1.4% vs 17.0%, P .01), postoperative transfusion requirement (0% vs 10.2%, P .01), and pneumonia (1.4% vs 10.2%, P = .05). After risk adjustment, an open procedure (vs video-assisted thoracoscopic surgery status) did not significantly affect the length of stay (effect 0.18; P = .10) or overall complication rate (odds ratio, 1.9; P = .12).In the setting of a comprehensive enhanced recovery protocol, patients undergoing video-assisted thoracoscopic surgery versus open lobectomy exhibited similar short-term outcomes. Surgical incision may have less impact on outcomes in the setting of a comprehensive thoracic enhanced recovery protocol.

Objectives Fibrocytes are integral in the development of fibroproliferative disease after lung transplantation. Undifferentiated fibrocytes (CD45+anti-collagen 1+CXCR4+) preferentially traffic by way of the CXCR4/CXCL12 axis and differentiate into smooth muscle actin-producing (CD45+CXCR4+α-smooth muscle actin+) cells. We postulated that an antibody directed against CXCL12 would attenuate fibrocyte migration and fibro-obliteration of heterotopic tracheal transplant allografts. Methods A total alloantigenic mismatch murine heterotopic tracheal transplant model of obliterative bronchiolitis was used. The mice were treated with either goat-anti-human CXCL12 F(ab′) 2 or goat IgG F(ab′) 2 . Buffy coat, bone marrow, and trachea allografts were collected and analyzed using flow cytometry. Tracheal luminal obliteration was assessed using hematoxylin-eosin and Direct Red 80 collagen stain. Results Compared with the controls, the anti-CXCL12–treated mice showed a significant decrease in tracheal allograft fibrocyte populations at 7 and 21 days after transplantation. Bone marrow and buffy coat aspirates showed the same trend at 7 days. In the anti-CXCL12–treated mice, there was a 35% decrease in luminal obliteration at 21 days (65% vs 100% obliterated; interquartile range, 38% vs 10%; P = .010) and decreased luminal collagen deposition at 21 and 28 days after transplantation ( P = .042 and P = .012, respectively). Conclusions Understanding the role of fibrocytes in airway fibrosis after lung transplantation could lead to a paradigm shift in treatment strategy. Anti-CXCL12 antibody afforded protection against infiltrating fibrocytes and reduced the deterioration of the tracheal allografts. Thus, the CXCR4/CXCL12 axis is a novel target for the treatment of fibro-obliteration after lung transplantation, and the quantification of fibrocyte populations could provide clinicians with a biomarker of fibrosis, allowing individualized drug therapy.

Evaluating giant paraesophageal hernia (GPEH) repair requires long-term follow-up. GPEH repair can have associated high recurrence rates, yet this incidence depends on how recurrence is defined. Our objective was to prospectively evaluate patients undergoing GPEH repair with 1-year follow-up.Patients undergoing elective GPEH repair between 2011 and 2014 were enrolled prospectively. Postoperatively, patients were evaluated at 1 month and 1 year. Radiographic recurrence was evaluated by barium swallow and defined as a gastroesophageal junction located above the hiatus. Quality of life was evaluated pre- and postoperatively with the use of a validated questionnaire.One-hundred six patients were enrolled. The majority of GPEH repairs were performed laparoscopically (80.2%), and 7.5% were redo repairs. At 1-year follow-up, 63.4% of patients were symptom free, and radiographic recurrence was 32.7%. Recurrence rate was 18.8% with standard definition (2 cm of stomach above the diaphragm). Quality of life scores at 1 year were significantly better after operative repair, even in patients with radiographic recurrence (7.0 vs 22.5 all patients, 13.0 vs 22.5 with recurrence; P .001). Patients with small radiographic recurrences have similar satisfaction and symptom severity to patients with2 cm recurrences.GPEH repair can be performed with low operative mortality and morbidity. The rate of recurrence at 1 year depends on the definition used. Patient satisfaction and symptom severity are similar between patients with radiographic and greater than 2 cm hernia recurrences. Longer follow-up and critical assessment of our results are needed to understand the true impact of this procedure and better inform perioperative decision making.

Objectives Ex vivo lung perfusion (EVLP) is a promising modality for the evaluation and treatment of marginal donor lungs. The optimal timing of EVLP initiation and the potential for rehabilitation of donor lungs with extended warm ischemic times is unknown. The present study compared the efficacy of different treatment strategies for uncontrolled non–heart-beating donor lungs. Methods Mature swine underwent hypoxic arrest, followed by 60 minutes of no-touch warm ischemia. The lungs were harvested and flushed with 4°C Perfadex. Three groups (n = 5/group) were stratified according to the preservation method: cold static preservation (CSP; 4 hours of 4°C storage), immediate EVLP (I-EVLP: 4 hours EVLP at 37°C), and delayed EVLP (D-EVLP; 4 hours of CSP followed by 4 hours of EVLP). The EVLP groups were perfused with Steen solution supplemented with heparin, methylprednisolone, cefazolin, and an adenosine 2A receptor agonist. The lungs then underwent allotransplantation and 4 hours of recipient reperfusion before allograft assessment for resultant ischemia–reperfusion injury. Results The donor blood oxygenation (partial pressure of oxygen/fraction of inspired oxygen ratio) before death was not different between the groups. The oxygenation after transplantation was significantly greater in the D-EVLP group than in the I-EVLP or CSP groups. The mean airway pressure, pulmonary artery pressure, and expression of interleukin-8, interleukin-1β, and tumor necrosis factor-α were all significantly reduced in the D-EVLP group. Post-transplant oxygenation exceeded the acceptable clinical levels only in the D-EVLP group. Conclusions Uncontrolled non–heart-beating donor lungs with extended warm ischemia can be reconditioned for successful transplantation. The combination of CSP and EVLP in the D-EVLP group was necessary to obtain optimal post-transplant function. This finding, if confirmed clinically, will allow expanded use of nonheart-beating donor lungs.

ObjectiveAdenosine A2A receptor activation after lung transplantation attenuates ischemia–reperfusion injury by reducing inflammation. However, the effect of adenosine A2A receptor activation in donor lungs before transplant remains ill defined. This study compares the efficacy of 3 different treatment strategies for adenosine A2A receptor agonist in a clinically relevant porcine lung transplantation model.MethodsMature porcine lungs underwent 6 hours of cold ischemia before allotransplantation and 4 hours of reperfusion. Five groups (n = 6/group) were evaluated on the basis of treatment with ATL-1223, a selective adenosine A2A receptor agonist: thoracotomy alone (sham), transplant alone (ischemia–reperfusion), donor pretreatment via ATL-1223 bolus (ATL-D), recipient treatment via ATL-1223 infusion (ATL-R), and a combination of both ATL-1223 treatments (ATL-D/R). Lung function and injury were compared.ResultsBlood oxygenation was significantly higher among ATL-D, ATL-R, and ATL-D/R groups versus ischemia–reperfusion (392.0 ± 52.5, 428.9 ± 25.5, and 509.4 ± 25.1 vs 77.2 ± 17.0 mm Hg, respectively, P .05).ConclusionsPretreatment of donor lungs with ATL-1223 was as efficacious as other treatment strategies in protecting against ischemia–reperfusion injury. If necessary, supplemental treatment of recipients with ATL-1223 may provide additional protection. These results support the development of pharmacologic A2AR agonists for use in human clinical trials for lung transplantation.

Objective The purpose of this study was to compare the outcomes and local control rates of patients with peripheral T1 and T2 non–small-cell lung cancer treated with stereotactic body radiation therapy. Methods The records of 40 consecutive patients treated with 3- or 5-fraction lung stereotactic body radiation therapy for peripheral, clinical stage I non–small-cell lung cancer were reviewed. Stereotactic body radiation therapy was delivered at a median dose of 60 Gy. Doses to organs at risk were limited based on the Radiation Therapy Oncology Group 0236 treatment protocol. Patients were staged clinically. Median follow was 12.5 months. Results Twenty-seven (67%) patients and 13 (33%) patients had T1 and T2 tumors, respectively. Thirty-seven (94%) patients were medically inoperable. Nine (23%) patients had chest wall pain after stereotactic body radiation therapy. Symptomatic pneumonitis developed in 4 (10%) patients. Increasing tumor size correlated with worse local control and overall survival. The median recurrence-free survival for T1 and T2 tumors was 30.6 months (95% confidence interval [CI], 26.9–34.2) and 20.5 months (95% CI, 14.3–26.5), respectively ( P = .038). Local control at 2 years was 90% and 70% in T1 and T2 tumors, respectively ( P = .03). The median survival for T1 and T2 tumors was 20 months (95% CI, 20.1–31.6) and 16.7 months (95% CI, 10.8–21.2), respectively ( P = .073). Conclusions Stereotactic body radiation therapy for T2 non–small-cell lung cancer has a higher local recurrence rate and trended toward a worse survival than did T1 lesions. Tumor size is an important predictor of response to stereotactic body radiation therapy and should be considered in treatment planning.

ObjectiveThe best current noninvasive surrogate for tumor biology is fluorodeoxyglucose positron emission tomography (FDG–PET). Both FDG–PET maximal standardized uptake values and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in non–small cell lung cancer (NSCLC). However, there are limited data correlating FDG–PET with tumor markers. The purpose of this study was to determine the correlation of tumor marker expression with FDG–PET maximal standardized uptake values in NSCLC.MethodsFDG–PET maximal standardized uptake values were calculated in patients with NSCLC (n = 149). No patient had induction chemoradiotherapy. Intraoperative NSCLC tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known NSCLC tumor markers (glucose transporter 1, p53, cyclin D1, epidermal growth factor receptor, and vascular endothelial growth factor). Each tumor marker was assessed independently by two pathologists using common grading criteria. Subgroup analysis based on histologic characteristics and regional nodal status was performed.ResultsFDG–PET correlated with T classification (P < .0001), N stage (P = .002), and greatest tumor dimension (P < .0001). In addition, increasing maximal standardized uptake values correlated with increased expression of glucose transporter 1 (P < .0001) and p53 (P = .04) in adenocarcinoma. Epidermal growth factor receptor expression correlated with maximal standardized uptake values without predilection for histologic subtype (P = .004).ConclusionFDG–PET maximal standardized uptake values correlate with an increased expression of glucose transporter 1 and p53 in lung adenocarcinoma, but not squamous cell cancer. Future studies attempting to correlate FDG–PET with tumor biology will need to consider the effect of different tumor histologic types.

Objectives Despite the potential limitation of organ availability, several surgical groups have advocated preferential bilateral lung transplantation because of its demonstrated long-term survival advantage. Comparative results for single and sequential double lung transplantation performed at a single center are evaluated to determine whether such a policy improves patient outcome. Methods A retrospective analysis of demographic and outcome data for patients undergoing lung transplantation was performed. Patients were grouped as single or double lung recipients and segregated into diagnostic categories according to the lung allocation scoring system. Era terciles were chosen on the basis of year of transplant, operating surgeon, and transplant volume. Results Between November 1990 and September 2005, 344 lung transplant procedures were performed in 339 patients. Over three time periods evaluated, the proportion of patients undergoing double lung transplant procedures increased. Overall survivals at 3 months and 1, 3, and 5 years were 89%, 79%, 60%, and 52%, respectively. After adjusting for lung recipient characteristics, survival after double lung transplantation was improved when compared with single lung transplantation ( P = .020). Overall patient survival among the three time periods was not significantly different at 30 days and 1 and 3 years despite increasing maximal donor organ ischemia times. Conclusions In this single-center study, despite longer median allograft ischemic times, as well as greater patient acuity as determined by listing diagnosis, overall early and midterm patient survival has remained higher than nationally reported figures. Bilateral lung transplantation in eligible patients is the procedure of choice.

Objective Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an adenosine A2A receptor agonist during ex vivo lung perfusion. Methods Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the adenosine A2A receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao 2 /Fio 2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins. Results Final Pao 2 /Fio 2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao 2 /Fio 2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao 2 /Fio 2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion. Conclusions After prolonged cold preservation, treatment of DCD donor lungs with an adenosine A2A receptor agonist during ex vivo lung perfusion enabled Pao 2 /Fio 2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation.

Objectives: Bronchiolitis obliterans is the greatest limitation to the long-term applicability of lung transplantation. Although alloimmune events are important, nonimmune events, such as gastroesophageal reflux, might contribute to lung injury and the development of bronchiolitis obliterans syndrome. Methods: We retrospectively studied the 396 patients who underwent lung transplantation at the Duke Lung Transplant Program from April 1992 to April 2002. Reflux was assessed for using an ambulatory 24-hour esophageal pH probe. Results: Reflux assessment with an esophageal pH probe was obtained in 128 patients after lung transplantation. Abnormal pH study results were present in 93 (73%) patients. Forty-three patients underwent a surgical fundoplication. There was no in-hospital or 30-day mortality in the patients undergoing fundoplication. At the time of fundoplication, 26 patients met the criteria for bronchiolitis obliterans syndrome. After fundoplication, 16 patients had improved bronchiolitis obliterans syndrome scores, with 13 of these patients no longer meeting the criteria for bronchiolitis obliterans syndrome. In patients at least 6 months after lung transplantation and 6 months after fundoplication, the forced expiratory volume in 1 second improved by an average of 24% (mean forced expiratory volume in 1 second before fundoplication, 1.87 L; mean forced expiratory volume in 1 second after fundoplication, 2.19 L/sec; P

Objective The prevalence of mediastinal lymph node metastases is unknown for patients with clinical N0 lung cancer who are thought to be at high risk for occult nodal metastases. Further, the utility of mediastinoscopy in these patients is unknown. We performed a prospective trial to evaluate the utility of routine cervical mediastinoscopy for patients who may be at high risk of occult nodal metastases. Methods From January 1, 2008, July 31, 2013, 90 patients with lung cancer with clinical stage T2N0 or T1N0 with standardized uptake value greater than 10 by positron emission tomography/computed tomography underwent routine cervical mediastinoscopy before lung resection. Biopsy of a minimum of 3 nodal stations at mediastinoscopy and a minimum of 4 nodal stations with lung resection was advised. The prevalence of nodal metastases at mediastinoscopy and lung resection was recorded. Results Some 64% of patients with lung cancer were male with a mean age of 67.3 years. A total of 81 patients had clinical T2N0 and 9 patients had T1N0 with standardized uptake value greater than 10. Mean tumor size was 4.3 ± 1.7 cm, and mean standardized uptake value was 13.5 ± 6.8. One patient (1.1%) had occult metastases detected at mediastinoscopy. A total of 86 patients underwent surgical resection; 4 patients (4.6%) were upstaged to pN2, and 18 patients (21%) were upstaged to pN1. Of 90 patients with clinically staged N0 lung cancer by positron emission tomography/computed tomography, 5.6% (5) were upstaged to pN2 and 20% (18) were upstaged to pN1 (total nodal upstaging = 25.6%). Conclusions Mediastinoscopy seems to have limited utility in these patients with T1 and T2 clinically staged N0 by positron emission tomography/computed tomography. Selective use of mediastinoscopy is recommended, along with thorough mediastinal lymph node evaluation in all patients at the time of lung cancer resection.

B lymphocytes are generally considered to be activators of the immune response; however, recent findings have shown that a subtype of B lymphocytes, regulatory B lymphocytes, play a role in attenuating the immune response. Bronchiolitis obliterans remains the major limitation to modern-day lung transplantation. The role of regulatory B lymphocytes in bronchiolitis obliterans has not been elucidated. We hypothesized that regulatory B lymphocytes play a role in the attenuation of bronchiolitis obliterans.We performed a standard heterotopic tracheal transplant model. Tracheas from Balb/c mice were transplanted into C57BL/6 recipients. Rapamycin treatment and dimethyl sulfoxide control groups were each treated for the first 14 days after the transplant. Tracheas were collected on days 7, 14, and 28 post-transplantation. Luminal obliteration was evaluated by hematoxylin-eosin staining and Picrosirius red staining. Immune cell infiltration and characteristics, and secretion of interleukin-10 and transforming growth factor-β1 were accessed by immunohistochemistry. Cytokines and transforming growth factor-β1 were measured using the Luminex assay (Bio-Rad, Hercules, Calif).The results revealed that intraperitoneal injection of rapamycin for 14 days after tracheal transplantation significantly reduced luminal obliteration on day 28 when compared with the dimethyl sulfoxide control group (97.78% ± 3.63% vs 3.02% ± 2.14%, P.001). Rapamycin treatment markedly induced regulatory B lymphocytes (B220(+)IgM(+)IgG(-)IL-10(+)TGF-β1(+)) cells when compared with dimethyl sulfoxide controls. Rapamycin treatment inhibited interleukin-1β, 6, 13, and 17 on days 7 and 14. Rapamycin also greatly increased interleukin-10 and transforming growth factor-β1 production in B cells and regulatory T lymphocytes infiltration on day 28.Mammalian target of rapamycin inhibition decreases the development of bronchiolitis obliterans via inhibition of proinflammatory cytokines and increasing regulatory B lymphocytes cell infiltration, which subsequently produces anti-inflammatory cytokines and upregulates regulatory T lymphocyte cells.

BackgroundThe Society of Thoracic Surgeons (STS) General Thoracic Surgery Database (GTSD) is the largest clinical thoracic surgical database in the United States. The purpose of the present study was to determine whether the GTSD esophagectomy outcomes are representative of nationwide outcomes by comparing them with other national clinical and administrative databases.MethodsFrom 2002 to 2008, esophageal cancer resection outcomes from the GTSD were compared with those from the National Surgery Quality Improvement Program (NSQIP) and Nationwide Inpatient Sample (NIS). The observed differences in patient characteristics and postoperative events were also analyzed.ResultsAnnual esophageal resection volumes have increased over time. However, as of 2008, the GTSD and NSQIP only capture a small proportion of resections performed nationally (36% and 11%, respectively). The median patient age and female gender were similar in all 3 databases. Mortality was significantly lower within the GTSD (3.2%) and NSQIP (2.6%) compared with the NIS (6.1%, P

Objectives Loss of epithelial cells is one of the key factors that lead to airway fibrosis. Loss of epithelial cells may decrease the barrier to host cell infiltration into the lumen, allowing deposition of extracellular matrix, with subsequent obliteration of the airway. The objective of this study was to determine whether injection of epithelial cells/progenitor cells from the recipient into the lumen of the donor trachea could prevent bronchiolitis obliterans (BO) in a mouse heterotopic tracheal transplantation (HTT) model. Methods A major histocompatibility complex class I and class II mismatch of mouse HTT model of BO was used. Epithelial cells from recipient mice were isolated and reinjected into the lumen of the allografts on day 3 after transplantation. Rag-1 knock-out and isografts were also performed as controls. The grafts were analyzed by immunohistochemistry and densitometric analysis. Results The results demonstrated that tracheal epithelium was lost by day 3, regenerated between 3 to 7 days, and was lost again in all allografts, but not in the isografts or in Rag-1 knock-out groups by day 12. The reconstituted epithelium was donor originated on day 7 based on green fluorescent protein staining. Furthermore, with the injection of recipient cells into the tracheal lumen, loss of the epithelium was not observed and the luminal obliteration was significantly less in the allografts. Conclusions Injection of recipient epithelial cells prevents the second phase of epithelial loss and significantly decreases BO development in an HTT model. Clinically, the use of injected recipient epithelial cells could be a novel treatment for BO.

ObjectivesIn 2005, the time-based waiting list for lung transplantation was replaced by an illness/benefit lung allocation score (LAS). Although short-term outcomes after transplantation have been reported to be similar before and after the new system, little is known about long-term results. The objective of this study was to evaluate the impact of LAS on the development of bronchiolitis obliterans syndrome as well as on overall 3-year and bronchiolitis obliterans syndrome–related survival.MethodsData obtained from the United Network for Organ Sharing were used to review 8091 patients who underwent lung transplantation from 2002 to 2008. Patients were stratified according to time of transplantation into those treated before initiation of the LAS (pre-LAS group, January 2002–April 2005, n = 3729) and those treated after implementation of the score (post-LAS group, May 2005–May 2008, n = 4362). Overall, 3-year survivals for patient groups were compared using a univariate analysis, Cox proportional hazards model to generate a relative risk, and Kaplan–Meier curve analyses.ResultsDuring the 3-year follow-up period, bronchiolitis obliterans syndrome developed in 22% of lung transplant recipients (n = 1801). Although the incidence of postoperative bronchiolitis obliterans syndrome development was similar between groups, post-LAS patients incurred fewer bronchiolitis obliterans syndrome–free days (609 ± 7.5 vs 682 ± 9; P

Objectives Vascular smooth muscle cells can undergo profound changes in phenotype, defined by coordinated repression of smooth muscle cell marker genes and production of matrix metalloproteinases in response to injury. However, little is known of the role of smooth muscle cells in aortic aneurysms. We hypothesized that smooth muscle cells undergo phenotypic modulation early in the development of aortic aneurysms. Methods Abdominal aortas from C57B6 mice (n = 79) were perfused with elastase or saline (control) and harvested at 1, 3, 7, or 14 days. Aortas were analyzed by means of quantitative polymerase chain reaction and immunohistochemistry for smooth muscle cell marker genes, including SM22A, smooth muscle α-actin, and matrix metalloproteinases 2 and 9. In complimentary experiments human aneurysms (n = 10) and control aorta (n = 10) were harvested at the time of surgical intervention and analyzed. Results By 14 days, aortic diameter was larger after elastase perfusion compared with control diameter (100% ± 9.6% vs 59.5% ± 18.9%, P = .0002). At 7 days, elastase-perfused mice had a 78% and 85% reduction in SM22α and smooth muscle α-actin expression, respectively, compared with that seen in control animals well before aneurysms were present, and these values remained repressed at 14 days. Immunohistochemistry confirmed less SM22α and smooth muscle α-actin in experimental aneurysms at 14 days in concert with increased matrix metalloproteinase 2 and 9 expression at 7 and 14 days. Similarly, human aneurysms had less SM22α and smooth muscle α-actin and increased matrix metalloproteinase 2 and 9 staining, compared with control values, as determined by means of quantitative polymerase chain reaction. Conclusions Aneurysms demonstrate smooth muscle cell phenotypic modulation characterized by downregulation of smooth muscle cell marker genes and upregulation of matrix metalloproteinases. These events in experimental models occur before aneurysm formation. Targeting smooth muscle cells to a reparative phenotype might provide a novel therapy in the treatment of aortic aneurysms.

Aneurysms of the pulmonary artery are a rare entity. In a review in 1947, Deterling and Clagett documented only 8 cases in more than 100,000 autopsies. Similarly, there were only 6 cases of pulmonary artery aneurysms in 4000 patients documented from 1785 to 1946. 1 These aneurysms are most commonly found with congenital heart anomalies, but acquired aneurysms may be associated with atherosclerosis, cystic medial necrosis, trauma, infections such as syphilis and endocarditis, or inflammatory processes such as giant cell arteritis. Although many patients with pulmonary artery aneurysms demonstrate pulmonary hypertension, this has not been proven to be a causative factor. In fact, most patients with pulmonary hypertension never have aneurysms. Symptoms are usually vague and may represent manifestations of the primary disease process or may be related to local compression. The disease process leads to rupture and death in approximately 30% of patients, with other deaths resulting from right-sided heart failure or pulmonary embolus. 2 Clinical Summary A 64-year-old man with a history of chronic obstructive pulmonary disease and pulmonary hypertension with giant pulmonary artery aneurysms came to our lung transplant center for evaluation. The pulmonary history was significant for tuberculosis treated at 8 months of age and an open lung biopsy performed in 1965 that showed pulmonary fibrosis. Preoperative pulmonary function tests revealed a forced expiratory volume in 1 second of 0.650 L (20% of predicted) and a diffusing capacity of lung for carbon monoxide of 28.9 (23% of predicted). Lung volumes were consistent with emphysema with a total lung capacity of 139% of predicted and a residual volume of 338% of predicted. Arterial blood gas analysis demonstrated a PaO2 of 53 mm Hg and a PaCO2 of 46 mm Hg on 21% inspired oxygen. The chest radiograph revealed enlarged bilateral pulmonary hila (Figure 1), and a computed tomographic (CT) scan of the chest performed in August 2000 showed a 6.2-cm main pulmonary artery with eccentric thrombus extending to the aneurysmal right and left pulmonary arteries (Figure 2). The lung parenchyma showed evidence of emphysema but no evidence of pulmonary fibrosis. Pretransplant cardiac blood pool imaging revealed decreased right and left ventricular ejection fractions at 29% and 39%, respectively. Cardiac catheterization showed pulmonary hypertension with a pulmonary artery pressure of 58/26 mm Hg, a cardiac index of 2.9 L/min, and no evidence of an intracardiac shunt. The patient was deemed a suitable candidate and was placed on the waiting list for a bilateral lung transplant. When donor lungs became available, he underwent a bilateral lung transplantation with reconstruction of the recipient pulmonary artery using donor aorta. The donor was an otherwise healthy 40-year-old patient who had died in a motor vehicle crash. However, the heart was not harvested because of poor left ventricular function. We were, therefore, able to harvest the entire thoracic aorta along with the lungs. The entire donor thoracic aorta was received with the specimen and was dissected from the lungs and placed in cold heparinized saline solution. The donor lungs were separated while the donor aorta was prepared. The patient was placed in the supine position, and the right and left sides of the chest were exposed through the fourth intercostal space using bilateral anterior thoracotomies and transverse division of the sternum. The lungs were then mobilized, and the aneurysm was seen extending from the origin of the main pulmonary artery into both pulmonary hila. The pericardium was opened, and the patient was placed on cardiopulmonary bypass with bicaval and ascending aortic cannulation. After this, both lungs were excised. When the pulmonary arteries were opened, a large amount of fibrinous clot was seen. The left lung was implanted first. The bronchial anastomosis

Objective: Pulmonary transplantation has become the preferred treatment for end-stage lung disease, but application of the procedure is limited because of a paucity of donors. One way to solve donor limitations is to use animal organs as a donor source or xenotransplantation. The current barrier to pulmonary xenotransplantation is the rapid failure of the pulmonary xenograft. Although antibodies are known to play a role in heart and kidney xenograft rejection, their involvement in lung dysfunction is less defined. This project was designed to define the role of antibodies in pulmonary graft rejection in a pig-to-baboon model. Methods: Orthotopic transgenic swine left lung transplants were performed in baboons depleted of antibodies by one of three techniques before transplantation: (1) ex vivo swine kidney perfusion, (2) total immunoglobulin-depleting column perfusion, and (3) ex vivo swine lung perfusion. Results were compared with those of transgenic swine lung transplants in unmodified baboons. Results: All three techniques of antibody removal resulted in depletion of xenoreactive antibodies. Only pretransplantation lung perfusion improved pulmonary xenograft function compared with lung transplantation in unmodified baboons. Conclusions: The pathogenesis of pulmonary injury in a swine-to-primate transplant model is different from that in renal and cardiac xenografts. Depletion of antibodies alone does not have a beneficial effect and may actually be detrimental. (J Thorac Cardiovasc Surg 2000;120:29-38)

ObjectiveCurrent clinical trials are investigating the role of stereotactic body radiation therapy (SBRT) versus sublobar resection for patients with non–small cell lung carcinoma (NSCLC) and marginal pulmonary function tests (M-PFTs). We compared the outcomes of patients undergoing lobectomy with M-PFTs characterized by 2 accepted M-PFT criteria.MethodsA total of 1,259 consecutive patients underwent lobectomy for NSCLC between 1999 and 2011. Patients were stratified into 2 classifications of M-PFT: American College of Surgeons Oncology Group (ACOSOG) Z4099/Radiation Therapy Oncology Group (RTOG) 1021 trial or American College of Chest Physicians (ACCP) criteria. There were 206 patients classified as having M-PFT according to ACOSOG Z4099/RTOG 1021 criteria and 131 patients classified as having M-PFT by ACCP criteria. The primary endpoints of the study were post-operative complications and survival.ResultsMedian follow-up was 3.8 years. Cox-proportional survival analysis found that pathologic stage (P

Objective Ischemia–reperfusion injury continues to plague the field of lung transplantation, resulting in suboptimal outcomes. In acute lung injury, processes such as ventilator-induced injury, sepsis, or acute respiratory distress syndrome, extravascular fibrin has been shown to promote lung dysfunction and the acute inflammatory response. This study investigates the role of the fibrinolytic cascade in lung ischemia–reperfusion injury and investigates the interplay between the fibrinolytic system and the inflammatory response. Methods Mice lacking the plasminogen activator inhibitor-1 gene (PAI-1 knock out, PAI-1 KO; and thus increased lysis of endogenous fibrin) and wild-type mice underwent in situ left lung ischemia and reperfusion. Fibrin content in the lung was evaluated by immunoblotting. Reperfusion injury was assessed by histologic and physiologic parameters. Proinflammatory mediators were measured in bronchoalveolar lavage fluid and plasma using enzyme-linked immunosorbent assays. Results Ischemia–reperfusion causes fibrin deposition in murine lungs. Less fibrin was seen in PAI-1 KO mice than in wild-type mice subjected to the same ischemia–reperfusion conditions. By histologic criteria, more evidence of ischemia–reperfusion injury was noted (thickening of the interstium, cellular infiltration in the alveoli) in the wild-type than in PAI-1 KO mice. Physiologic parameters also revealed more ischemia–reperfusion injury in the wild-type than in PAI-1 KO mice. Cytokine and chemokines were elevated more in the wild-type group than the PAI-1 KO group. Conclusions Lung ischemia–reperfusion injury triggers fibrin deposition in the murine lungs and fibrin creates a proinflammatory environment. Preventing fibrin deposition may reduce ischemia–reperfusion injury and inflammation. This finding may lead to novel treatment strategies for ischemia–reperfusion.

ObjectivePulmonary resections are performed at thoracic residency (TR), general surgery residency (GSR), no surgery residency, and no residency hospitals. We hypothesize that morbidity and mortality for these procedures are different between hospitals and that operations performed at TR teaching hospitals have superior results.MethodsRecords of adults who underwent pneumonectomy, lobar, segmentectomy, and nonanatomic wedge resections (N = 498,099) were evaluated in an all-payer inpatient database between 2003 and 2009. Hospital teaching status was determined by linkage to Association of American Medical College's Graduate Medical Education Tracking System. Multiple hierarchical regression models examined the in-hospital mortality, occurrence of any complication, and failure to rescue.ResultsThe mean annual pulmonary resection volume among hospitals was TR (16%), GSR (17%), no surgery residency (28%), and no residency (39%). Unadjusted mortality for all procedures was lowest at TR hospitals (P