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Background: There is a critical shortage of donor lungs for transplantation. We previously developed a parsimonious, highly discriminatory 9-variable Lung Donor (LUNDON) acceptability score. Here we assessed the utility of this score as a tool for improving lung recovery rates for transplantation., Methods: We examined all brain-dead donors between 2014 and 2020 from 3 US organ procurement organizations and validated the score's predictive performance. We examined the trajectory of donors with low (<40) and high (>60) initial LUNDON scores, their corresponding lung recovery rates, factors contributing to score improvement using multivariable regression models, and 1-year post-transplant recipient survival., Results: Overall lung recovery was 32.4% (1410 of 4351). Validation of the LUNDON score in our cohort revealed a C statistic of 0.904 and required intercept calibration. Low initial LUNDON donors that improved to a high final score had an increase in lung recovery rate from 29.3% (1100 of 3765) to 86.8% (441 of 508), associated with lower body mass index, management in a specialized donor care facility (SDCF), and more bronchoscopies. Donors with high initial and final LUNDON scores had a lung recovery rate of 85.2% (98 of 115), associated with shorter length of hospital stay. One-year survival was similar in recipients of low-to-high versus high-to-high LUNDON score donors (0.89 vs 0.84; P = .2)., Conclusions: The LUNDON score performs well as a predictor of lung recovery in a contemporary cohort but may require organ procurement organization-specific calibration. SDCF care, increasing use of bronchoscopy, and decreasing the time from brain death to organ procurement may improve lung utilization. The LUNDON score can be used to guide donor management to expand the donor pool., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Approximately 3 million Americans served in the armed forces during the Vietnam War. Veterans have a higher incidence rate of lung cancer compared with the general population, which may be related to exposures sustained during service. Agent Orange, one of the tactical herbicides used by the armed forces as a means of destroying crops and clearing vegetation, has been linked to the development of several cancers including non-small cell lung cancer. However, traditional risk models of lung cancer survival and recurrence often do not include such exposures. We aimed to examine the relationship between Agent Orange exposure and overall survival and disease recurrence for surgically treated stage I non-small cell lung cancer., Methods: We performed a retrospective cohort study using a uniquely compiled dataset of US Veterans with pathologic I non-small cell lung cancer. We included adult patients who served in the Vietnam War and underwent surgical resection between 2010 and 2016. Our 2 comparison groups included those with identified Agent Orange exposure and those who were unexposed. We used multivariable Cox proportional hazards and Fine and Gray competing risk analyses to examine overall survival and disease recurrence for patients with pathologic stage I disease, respectively., Results: A total of 3958 Vietnam Veterans with pathologic stage I disease were identified (994 who had Agent Orange exposure and 2964 who were unexposed). Those who had Agent Orange exposure were more likely to be male, to be White, and to live a further distance from their treatment facility (P < .05). Tumor size distribution, grade, and histology were similar between cohorts. Multivariable Cox proportional hazards modeling identified similar overall survival between cohorts (Agent Orange exposure hazard ratio, 0.97; 95% CI, 0.86-1.09). Patients who had Agent Orange exposure had a 19% increased risk of disease recurrence (hazard ratio, 1.19; 95% CI, 1.02-1.40)., Conclusions: Veterans with known Agent Orange exposure who undergo surgical treatment for stage I non-small cell lung cancer have an approximately 20% increased risk of disease recurrence compared with their nonexposed counterparts. Agent Orange exposure should be taken into consideration when determining treatment and surveillance regimens for Veteran patients., (Copyright © 2023. Published by Elsevier Inc.)

Objective: National and institutional data suggest an increase in organ discard rate (donor lungs procured but not implanted) after a new lung allocation policy was introduced in 2017. However, this measure does not include on-site decline rate (donor lungs declined intraoperatively). The objective of this study is to examine the impact of the allocation policy change on on-site decline., Methods: We used a Washington University (WU) and our local organ procurement organization (Mid-America Transplant [MTS]) database to abstract data on all accepted lung offers from 2014 to 2021. An on-site decline was defined as an event in which the procuring team declined the organs intraoperatively, and the lungs were not procured. Logistic regression models were used to investigate potentially modifiable reasons for decline., Results: The overall study cohort comprised 876 accepted lung offers, of which 471 donors were at MTS with WU or others as the accepting center and 405 at other organ procurement organizations with WU as the accepting center. At MTS, the on-site decline rate increased from 4.6% to 10.8% (P = .01) after the policy change. Given the greater likelihood of non-local organ placement and longer travel distance after policy change, the estimated cost of each on-site decline increased from $5727 to $9700. In the overall group, latest partial pressure of oxygen (odds ratio [OR], 0.993; 95% confidence interval [CI], 0.989-0.997), chest trauma (OR, 2.474; CI, 1.018-6.010), chest radiograph abnormality (OR, 2.902; CI, 1.289-6.532), and bronchoscopy abnormality (OR, 3.654; CI, 1.813-7.365) were associated with on-site decline, although lung allocation policy era was unassociated (P = .22)., Conclusions: We found that nearly 8% of accepted lungs are declined on site. Several donor factors were associated with on-site decline, although lung allocation policy change did not have a consistent impact on on-site decline., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The decision to perform single lung transplants or double lung transplants is usually made before the operation. We have previously reported that a proportion of single lung transplants were unexpectedly performed in the setting of an aborted double lung transplant, and these patients may be at a higher risk of worse short-term outcomes. Long-term outcomes in unplanned single lung transplants remain unknown., Methods: We analyzed a single-center database of lung transplants from 2000 to 2020. Single lung transplants were classified into planned and unplanned groups after reviewing operative notes. Root cause analysis was performed for unplanned single lung transplants., Results: Of the 1326 lung transplants, 1265 (95%) were double lung transplants and 61 (5%) were single lung transplants (22 planned [36%], 39 unplanned [64%]). Underlying indications for transplant were significantly different; planned single lung transplant: chronic obstructive pulmonary disease (55%) and idiopathic pulmonary fibrosis (45%); unplanned single lung transplants: chronic obstructive pulmonary disease (23%), idiopathic pulmonary fibrosis (39%), and bronchiolitis obliterans syndrome (13%). The primary reasons for unplanned single lung transplant were donor-related (3, 7.7%), recipient-related (31, 80%), and donor and recipient-related factors (5, 13%). Unplanned single lung transplants were more likely to require cardiopulmonary bypass during the operation (planned: 4/22, 18% vs unplanned: 20/39, 51%) but had shorter ischemic times (planned: 251 ± 58 minutes vs unplanned: 221 ± 48 minutes). The 5-year overall survival was 53% in the planned and 58% in the unplanned groups, respectively (P = .323). No difference in chronic lung allograft dysfunction-free survival (P = .995) was observed., Conclusions: Unplanned single lung transplants in the setting of aborted double lung transplant may be associated with acceptable long-term outcomes., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: Patient-reported outcomes (PROs) are critical tools for evaluating patients before and after lung cancer resection. In this study, we assessed patient-reported pain, dyspnea, and functional status up to 1 year postoperatively., Methods: This study included patients who underwent surgery for non-small cell lung cancer at a single institution (2017-2020). We collected PROs using the National Institutes of Health Patient Reported Outcome Measurement Information System (PROMIS). Data were prospectively collected and merged with our institutional Society of Thoracic Surgeons data. Using multivariable linear mixed effect models, we compared PROMIS scores for preoperative and several postoperative visits., Results: From 2017 until 2020, 334 patients underwent lung cancer resection with completed PROMIS assessments. Pain interference, physical function, and dyspnea severity scores were worse 1 month after surgery (P < .001). Pain interference and physical function scores returned to baseline by 6 months after surgery. However, dyspnea severity scores remained persistently worse up to 1 year after surgery (1-month difference, 8.8 ± 1.9; 6-month difference, 3.6 ± 2.2; 1-year difference, 4.9 ± 2.8; P < .001). Patients who received a thoracotomy had worse physical function and pain interference scores 1 month after surgery compared with patients who received a minimally invasive operation; however, there were no differences in PROs by 6 months after surgery., Conclusions: PROs are important metrics for assessing patients before and after lung cancer resection. Patients may report persistent dyspnea up to 1 year after resection. Additionally, patients undergoing thoracotomy initially report worse pain and physical function but these impairments improve by 6 months after surgery., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to recognize clinically meaningful differences in lung transplant outcomes based on local or distant lung procurement. This could identify if the lung allocation policy change would influence patient outcomes., Methods: This single-center retrospective cohort study analyzed adult patients who underwent lung transplant from 2006 to 2017. Donor and recipient data were abstracted from a collaborative, prospective registry shared by our local organ procurement organization, and tertiary medical center. Short-term outcomes, 1-year survival, and hospitalization costs were compared between local and distant lung transplants defined by donor service area., Results: Of the 722 lung transplants performed, 392 (54%) had local donors and 330 (46%) had distant donors. Donors were similar in age and cause of death. Recipients were significantly different in diagnosis and local recipients had lower median lung allocation scores (local, 37.3 and distant, 44.9; P < .01). Distant lung transplants had longer total ischemic times (local, 231 ± 52 minutes and distant, 313 ± 48 minutes; P < .01). The rate of major complications, length of hospital stay, and 1-year survival were similar between groups. Distant lung transplants were associated with higher median overall cost (local, $183,542 and distant, $229,871; P < .01). Local lung transplants were more likely to be performed during daytime (local, 333 out of 392 [85%] and distant, 291 out of 330 [61%]; P < .01)., Conclusions: Local lung transplants are associated with shorter ischemic times, lower cost, and greater likelihood of daytime surgery. Short- and intermediate-term outcomes are similar for lung transplants from local and distant donors. The new lung allocation policy, with higher proportion of distant lung transplants, is likely to incur greater costs but provide similar outcomes., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Chest computed tomography (CT) imaging is being increasingly used for potential lung donor assessment. However, the efficacy of CT imaging in this setting remains unknown. We hypothesize that chest CT imaging independently affects the decision-making process in donor lung utilization., Methods: We conducted a retrospective cohort study of all adult donation after brain death donors managed through our local organ procurement organization from June 2011 to November 2016. An experienced thoracic radiologist independently reviewed donor chest CT and chest x-ray images in a blinded, standardized manner to determine the presence of structural lung disease (eg, emphysema, interstitial lung disease [ILD]) and acute abnormalities (eg, traumatic lung injury [TLI]). Distinct models of lung utilization were fit to groups with initial partial pressure of oxygen (iPaO 2 ) ≤300 mm Hg (suboptimal) and iPaO 2 >300 mm Hg (optimal)., Results: The organ procurement organization managed 753 donors during the study period, with a lung utilization rate ([lung donors/all organ donors] × 100) of 36.5% (275 of 753). Four hundred forty-five (59.1%) donors received chest CT imaging, revealing emphysema (13.7%), ILD (2.5%), and TLI (7.2%). In univariate analysis, findings of TLI (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.08-4.61) were positively associated with lung utilization, whereas findings of emphysema (OR, 0.18; CI, 0.08-0.40) were negatively associated with utilization. In multivariate analysis, CT findings of emphysema (OR, 0.21; CI 0.08-0.54) remained negatively associated with utilization. No potential donors with CT findings of ILD became lung donors. After controlling for chest x-ray findings, chest CT imaging findings of structural lung disease remained negatively associated with utilization (P = .0001). Lung utilization rate in the suboptimal and optimal iPaO 2 populations was 35.1% and 41.4%, respectively, and CT findings of emphysema had a significant association with nonutilization in both groups., Conclusions: In the evaluation of potential lung donors, chest CT imaging findings of structural lung disease, such as emphysema and ILD, have a significant negative association with lung utilization. Our findings suggest that chest CT imaging might be an important adjunct to conventional lung donor assessment criteria., (Copyright © 2018 The American Association for Thoracic Surgery. All rights reserved.)

Objective: Routine surveillance imaging for patients with resected non-small cell lung cancer is standard for the detection of disease recurrence and new primary lung cancers. However, surveillance intensity varies widely in practice, and its impact on long-term outcomes is poorly understood. We hypothesized that surveillance intensity was not associated with 5-year overall survival in patients with resected stage I non-small cell lung cancer. Additionally, we examined patterns of recurrence and new primary lung cancer development., Methods: Cancer registrars at Commission on Cancer accredited institutions re-abstracted records to augment National Cancer Database patient data with information on comorbidities, imaging surveillance including intent and result of imaging, and recurrence (2007-2012). Pathologic stage I non-small cell lung cancer patients undergoing computed-tomography surveillance were placed into three imaging surveillance groups based on clinical practice guidelines: high intensity (3 month), moderate intensity (6 month), and low intensity (annual). Kaplan Meier analysis and Cox regression were used to compare overall survival among the three surveillance groups., Results: 2442 patients were identified, with 805 (33%), 1216 (50%), and 421 (17%) patients in the high, moderate, and low surveillance intensity groups, respectively. Five-year overall survival was similar between intensity groups (p=0.547). Surveillance on asymptomatic patients detected 210 (63%) cases of locoregional recurrences and 128 (72%) cases of new primary lung cancer., Conclusions: In a unique national dataset of long-term outcomes for stage I non-small cell lung cancer, surveillance intensity was not associated with 5-year overall survival., Competing Interests: Conflicts of Interest: No conflicts of interest to disclose.

Objectives: We compared the effectiveness of upfront esophagectomy versus induction chemoradiation followed by esophagectomy for overall survival in patients with clinical T2N0 (cT2N0) esophageal cancer. We also assessed the influence of the diagnostic uncertainty of endoscopic ultrasound on the expected benefit of chemoradiation., Methods: We created a decision analysis model representing 2 treatment strategies for cT2N0 esophageal cancer: upfront esophagectomy that may be followed by adjuvant therapy for upstaged patients and induction chemoradiation for all patients with cT2N0 esophageal cancer followed by esophagectomy. Parameter values within the model were obtained from published data, and median survival for pathologic subgroups was derived from the National Cancer Database. In sensitivity analyses, staging uncertainty of endoscopic ultrasound was introduced by varying the probability of pathologic upstaging., Results: The baseline model showed comparable median survival for both strategies: 48.3 months for upfront esophagectomy versus 45.9 months for induction chemoradiation and surgery. The sensitivity analysis demonstrated induction chemoradiation was beneficial, with probability of upstaging > 48.1%, which is within the published range of 32% to 65% probability of pathologic upstaging after cT2N0 diagnosis. The presence of any of 3 key variables (size larger than 3 cm, high grade, or lymphovascular invasion) was associated with > 48.1% risk of upstaging, thus conferring a survival advantage to induction chemoradiation., Conclusions: The optimal treatment strategy for cT2N0 esophageal cancer depends on the accuracy of endoscopic ultrasound staging. High-risk features that confer increased probability of upstaging can inform clinical decision making to recommend induction chemoradiation for select cT2N0 patients., (Copyright © 2018 The American Association for Thoracic Surgery. All rights reserved.)

Objectives: Stage I non-small cell lung cancer traditionally is treated with lobectomy. Sublobar resection and stereotactic body radiation therapy provide alternative treatments for higher-risk groups. The purpose of this study was to determine the national treatment trends for stage I lung cancer., Methods: The National Cancer Database was queried for patients with clinical stage I non-small cell lung cancer between 1998 and 2012. Patients were compared across treatment groups, and trends in treatment and disease were evaluated over the 15-year time period., Results: The National Cancer Database contained 369,931 patients with clinical stage I non-small cell lung cancer. After removing patients who received chemotherapy as a first course of treatment and patients with pathologic stage IV, 357,490 patients were analyzed. The first recorded cases of stereotactic body radiation therapy are in 2003 and rapidly increased to 6.6% (2063) of all patients treated in 2012. The number of diagnoses of stage I non-small cell lung cancer steadily increased over the 15-year period, whereas the rate of lobectomy decreased from 55% in 1998 to 50% in 2012 (P < .001). Most of the decrease in lobectomy can be explained by the increase in the rate of sublobar resection from 12% to 17% (P < .001). The percentage of untreated patients remained stable at approximately 7% (P = .283)., Conclusions: Although the number of stage I non-small cell lung cancer cases continues to increase, lobectomy rates are decreasing while sublobar resection and stereotactic body radiation therapy rates are increasing. Although the increasing popularity of alternative therapies to lobectomy for treatment of stage I non-small cell lung cancer should allow more patients to undergo treatment, we did not observe this trend in the data., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: 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., Methods: 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., Results: 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 with >2 cm recurrences., Conclusions: 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., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: Postoperative readmission is an increasingly scrutinized quality metric that affects patient satisfaction and cost. Even more important is its implication for short-term prognosis. The purpose of this study is to characterize postesophagectomy readmissions and determine their relationship with subsequent 90-day mortality., Methods: Data were extracted for esophagectomy patients from the linked SEER-Medicare Registry (2000-2009), which provides longitudinal information about Medicare beneficiaries who have cancer. We assessed demographics, comorbidities, 30-day readmission, and 90-day mortality. Readmitting facility and diagnoses were identified. A hierarchic multivariable regression model clustered at the hospital level assessed the relationship between readmission within 30 days of discharge and 90-day mortality., Results: We identified 1543 patients discharged alive after esophagectomy. Among patients discharged alive, the readmission rate was 319 of 1543 (20.7%); 107 of 319 (33.5%) readmissions were to facilities that did not perform the index operation. Mortality rate at 90 days among patients discharged alive was 98 of 1543 (6.4%). Readmission was associated with a 4-fold increase in mortality (16.3% vs 3.8%, P < .001). Using multivariable regression, readmission was the strongest predictor of mortality (odds ratio 6.64, P < .001), with a stronger association than age, Charlson score, and index length of stay. Readmission diagnoses with the highest mortality rates were those associated with pulmonary, gastrointestinal, and cardiovascular diagnoses., Conclusions: Patients readmitted within 30 days of discharge after esophagectomy are at exceptionally high risk for early mortality. Early recognition of life-threatening readmission diagnoses is essential to providing optimal care., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To review the published literature using propensity scoring, describe shortcomings in the use of this technique, and provide conceptual background for understanding and correctly implementing studies that use propensity matching., Methods: We survey the published statistical literature and make recommendations for a set of standard criteria for studies that use propensity matching. We evaluated adherence to these criteria in recent publications in the Journal of Thoracic and Cardiovascular Surgery and determined how well the standards were applied., Results: We found that studies that use propensity matching are rarely documented well enough to be convincing in their results. When documentation is available, statistical shortcomings are common., Conclusions: Improved statistical practice is needed when using propensity scoring. This article suggests standard criteria for using this method in Journal publications., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., (Published by Elsevier Inc.)

Objectives: Postoperative readmission affects patient care and healthcare costs. There is a paucity of nationwide data describing the clinical significance of readmission after thoracic operations. The purpose of this study was to evaluate the relationship between postoperative readmission and mortality after lung cancer resection., Methods: Data were extracted for patients undergoing lung cancer resection from the linked Surveillance Epidemiology and End Results-Medicare registry (2006-2011), including demographics, comorbidities, socioeconomic factors, readmission within 30 days from discharge, and 90-day mortality. Readmitting facility and diagnoses were identified. A hierarchical regression model clustered at the hospital level identified predictors of readmission., Results: We identified 11,432 patients undergoing lung cancer resection discharged alive from 677 hospitals. The median age was 74.5 years, and 52% of patients received an open lobectomy. Thirty-day readmission rate was 12.8%, and 28.3% of readmissions were to facilities that did not perform the original operation. Readmission was associated with a 6-fold increase in 90-day mortality (14.4% vs 2.5%, P<.001). The most common readmitting diagnoses were respiratory insufficiency, pneumonia, pneumothorax, and cardiac complications. Patient factors associated with readmission included resection type; age; prior induction chemoradiation; preoperative comorbidities, including congestive heart failure and chronic obstructive pulmonary disease; and low regional population density., Conclusions: Factors associated with early readmission after lung cancer resection include patient comorbidities, type of operation, and socioeconomic factors. Metrics that only report readmissions to the operative provider miss one-fourth of all cases. Readmitted patients have an increased risk of death and demand maximum attention and optimal care., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Current 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., Methods: A 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., Results: Median follow-up was 3.8 years. Cox-proportional survival analysis found that pathologic stage (P < .001), age (P < .001), and higher Zubrod functional status (P < .001) were independent predictors of mortality. Using multivariable analysis for major morbidity, M-PFT status was not associated with the development of a major complication following lobectomy (P = .68). M-PFT classification was not an independent predictor of mortality when controlling for other variables (ACOSOG Z4099/RTOG 1021 [P = .34]; ACCP criteria [P = .83]). A composite major morbidity analysis for major morbidity following lobectomy showed no association between clinicopathologic variables or M-PFTs and the occurrence of a major postoperative morbidity., Conclusions: In carefully selected patients with M-PFTs, lobectomy for NSCLC can be performed with acceptable morbidity and mortality. These results need to be considered when deciding if a patient should undergo lobectomy or other therapies for resectable NSCLC., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Pulmonary 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., Methods: Records 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., Results: The 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 < .001). Likewise, any complication was least likely to occur at TR hospitals (P < .001). After case-mix adjustment, the risk of any complication after segmentectomy or nonanatomic wedge resection was lower at TR hospitals than in GSR hospitals (P < .001). Among pneumonectomy recipients, TR hospitals reduced the adjusted odds ratio of failure to rescue by more than 25% compared with no surgery residency (P < .001). Likewise, in patients who underwent pneumonectomy, TR centers were associated with reducing the odds ratio of death by more than 30% compared with GSR hospitals (P < .001)., Conclusions: In comparison with other hospitals, including GSR hospitals, TR hospitals have lower morbidity and mortality. These results support using hospitals with a TR as an independent prognostic indicator of outcomes in pulmonary resections., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: The 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., Methods: From 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., Results: Annual 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 < .001). The median length of stay was lower in the GTSD (10 days) than in either the NSQIP (12 days) and NIS (12 days, P < .001)., Conclusions: The STS GTSD reports outstanding mortality results and hospital length of stay for esophageal cancer resection. However, the surgical outcomes from the STS GTSD are not representative of the national results from programs not participating in the database. These results establish a reference for future esophagectomy comparisons and highlight the importance of increased participation and use of the STS GTSD., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Recent trials comparing on-pump (CABG) with off-pump coronary artery bypass grafting (OPCAB) have been criticized by those who believe that surgeon inexperience may explain the apparent worse outcomes for OPCAB. However, the true effect of surgeon volume on outcomes after OPCAB remains unknown. The purpose of this study was to examine the effect of surgeon volume on risk-adjusted mortality after OPCAB., Methods: From 2003 to 2007, 709,483 patients underwent coronary artery bypass grafting operations (CABG = 439,253; OPCAB = 270,230) within the Nationwide Inpatient Sample database. Hierarchic generalized linear regression modeling with spline functions for annual individual operating surgeon volume was used to assess the relationship between annual surgeon volume and inpatient mortality, adjusted for comorbid disease and other potential confounders., Results: OPCAB was performed in 38.1% of coronary artery bypass grafting operations. The average age for those undergoing OPCAB was 66.1 ± 11.1 years, and female patients accounted for 29.3% of operations with 1-vessel (20.4%), 2-vessel (36.6%), 3-vessel (20.5%), or 4 vessels or more (13.6%). Median surgeon volume for OPCAB was 105 (56-156) operations per year. A highly significant nonlinear relationship between surgeon volume and risk-adjusted mortality was observed for OPCAB operations (P < .01). Specifically, an estimated 5% decrease in the absolute probability of death occurred after OPCAB performed by the surgeons with the highest volume, which is greater than the 3% estimated decrease for conventional CABG. Of note, the effect of surgeon volume on mortality was significantly less than other risk factors, such as the presence of heart failure, renal failure, type of bypass conduit, and gender., Conclusions: A significant surgeon volume-outcome relationship exists for mortality after OPCAB with a threshold of more than 50 operations per year. However, the contribution of surgeon volume to the probability of death is incrementally small compared with other patient and operative characteristics. This demonstrates that outcomes after OPCAB are more dependent on patient risk factors than on surgeon volume., (Copyright © 2012. Published by Mosby, Inc.)

Objectives: In 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., Methods: Data 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., Results: During 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 <.0001; log-rank test P = .0108) than did pre-LAS patients. Overall 3-year survival was lower in post-LAS patients and approached statistical significance (P = .05). Similarly, bronchiolitis obliterans syndrome-related survival was worse for patients in the post-LAS group (log-rank test P = .01)., Conclusions: In the current LAS era, lung transplant recipients have significantly fewer bronchiolitis obliterans syndrome-free days after 3-year follow-up. Compared with the pre-LAS population, overall and bronchiolitis obliterans syndrome-related survival appears worse in the post-LAS era. Limitation of known risk factors for development of bronchiolitis obliterans syndrome-may prove even more important in this patient population., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

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., (2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: Severe reperfusion injury after lung transplantation has mortality rates approaching 40%. The purpose of this investigation was to identify whether our improved 1-year survival after lung transplantation is related to a change in reperfusion injury., Methods: We reported in March 2000 that early institution of extracorporeal membrane oxygenation can improve lung transplantation survival. The records of consecutive lung transplant recipients from 1990 to March 2000 (early era, n = 136) were compared with those of recipients from March 2000 to August 2006 (current era, n = 155). Reperfusion injury was defined by an oxygenation index of greater than 7 (where oxygenation index = [Percentage inspired oxygen] x [Mean airway pressure]/[Partial pressure of oxygen]). Risk factors for reperfusion injury, treatment of reperfusion injury, and 30-day mortality were compared between eras by using chi(2), Fisher's, or Student's t tests where appropriate., Results: Although the incidence of reperfusion injury did not change between the eras, 30-day mortality after lung transplantation improved from 11.8% in the early era to 3.9% in the current era (P = .003). In patients without reperfusion injury, mortality was low in both eras. Patients with reperfusion injury had less severe reperfusion injury (P = .01) and less mortality in the current era (11.4% vs 38.2%, P = .01). Primary pulmonary hypertension was more common in the early era (10% [14/136] vs 3.2% [5/155], P = .02). Graft ischemic time increased from 223.3 +/- 78.5 to 286.32 +/- 88.3 minutes in the current era (P = .0001). The mortality of patients with reperfusion injury requiring extracorporeal membrane oxygenation improved in the current era (80.0% [8/10] vs 25.0% [3/12], P = .01)., Conclusion: Improved early survival after lung transplantation is due to less severe reperfusion injury, as well as improvements in survival with extracorporeal membrane oxygenation.

Objective: The 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., Methods: FDG-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., Results: FDG-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)., Conclusion: FDG-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.

Objective: Effects of daclizumab and antithymocyte globulin induction on acute rejection, bronchiolitis obliterans syndrome, and survival after lung transplantation are unknown. We hypothesized that daclizumab results in less acute rejection and bronchiolitis obliterans and better survival than antithymocyte globulin., Methods: Consecutive adult lung transplants (n = 163) at the University of Virginia from January 1998 to May 2006 were reviewed. Antithymocyte globulin induction was routinely performed before January 2002 (65 patients), after which all patients received daclizumab (98 patients). Estimates of cumulative event rate of acute rejection, bronchiolitis obliterans, and death were calculated by Kaplan-Meier method and between-group differences compared by log-rank test. Cox proportional hazards models were fitted to assess treatment effects adjusted for covariates., Results: Groups were similar in demographics and preoperative and intraoperative risk factors. Maintenance immunosuppression changed during the study, and mycophenolate mofetil was more commonly given to patients receiving daclizumab. By Kaplan-Meier method, daclizumab was associated with significantly less acute rejection (P = .002), less bronchiolitis obliterans (P = .02), and improved overall survival (P = .04). Induction agent was highly associated with acute rejection (P = .002), bronchiolitis obliterans (P = .02), and mortality (P = .05); antimetabolite agent was associated only with acute rejection (P = .01). Adjusting for covariates, induction agent remained significantly predictive for acute rejection (P = .02) and bronchiolitis obliterans (P = .05), approaching significance for survival (P = .07)., Conclusion: Lung transplant recipients receiving daclizumab for induction had significantly less acute rejection and bronchiolitis obliterans than those receiving antithymocyte globulin, with possibly improved survival. Improvements in acute rejection may have been confounded by the use of mycophenolate mofetil.

Objective: The lung allocation score restructured the distribution of scarce donor lungs for transplantation. The algorithm ranks waiting list patients according to medical urgency and expected benefit after transplantation. The purpose of this study was to evaluate the impact of the lung allocation score on short-term outcomes after lung transplantation., Methods: A multicenter retrospective cohort study was performed with data from 5 academic medical centers. Results of patients undergoing transplantation on the basis of the lung allocation score (May 4, 2005 to May 3, 2006) were compared with those of patients receiving transplants the preceding year before the lung allocation score was implemented (May 4, 2004, to May 3, 2005)., Results: The study reports on 341 patients (170 before the lung allocation score and 171 after). Waiting time decreased from 680.9 +/- 528.3 days to 445.6 +/- 516.9 days (P < .001). Recipient diagnoses changed with an increase in idiopathic pulmonary fibrosis and a decrease in emphysema and cystic fibrosis (P = .002). Postoperatively, primary graft dysfunction increased from 14.1% (24/170) to 22.9% (39/171) (P = .04) and intensive care unit length of stay increased from 5.7 +/- 6.7 days to 7.8 +/- 9.6 days (P = .04). Hospital mortality and 1-year survival were the same between groups (5.3% vs 5.3% and 90% vs 89%, respectively; P > .6), Conclusions: This multicenter retrospective review of short-term outcomes supports the fact that the lung allocation score is achieving its objectives. The lung allocation score reduced waiting time and altered the distribution of lung diseases for which transplantation was done on the basis of medical necessity. After transplantation, recipients have significantly higher rates of primary graft dysfunction and intensive care unit lengths of stay. However, hospital mortality and 1-year survival have not been adversely affected.

Objective: Lung retransplantation is a controversial practice due to increased morbidity and mortality and the scarcity of available donor organs. Living donor lobar lung transplantation increases the number of available donor organs and facilitates a more organized procedure than traditional cadaveric donation for this complex reoperation. The purpose of this study was to evaluate our experience with pediatric lung retransplantation and to compare the outcomes of living donor lobar lung transplantation with cadaveric donation., Methods: Retrospective review of a prospectively collected database identified 39 children who underwent lung retransplantation from 1991 to 2004. Retransplantation was performed with living donor lobar lung transplantation in 13 patients and cadaveric donation in 26 patients. Short- and long-term outcomes were compared between the 2 groups., Results: Perioperative mortality was 1/13 (7.7%) in the patients who had living donor lobar lung transplantation versus 11/26 (42.3%) in the cadaveric donation group (P = .03). Five-year survival for living donor lobar lung transplantation and cadaveric donation was 40.4% and 29.7%, respectively (P = .27). Both groups had a significant improvement in their forced expiratory volume in 1 second 6 months after retransplantation (P < .001). Multivariate analysis identified the use of cadaveric donation (relative risk = 6.16, P = .001) and early graft dysfunction (relative risk = 6.19, P = .001) as the major independent predictors of decreased survival following retransplantation., Conclusions: Living donor lobar lung transplantation reduces perioperative mortality and is an independent predictor of improved survival following pediatric lung retransplantation. This strategy offers significant benefit for this high-risk group and preserves the limited supply of donor lungs for other children at risk of dying while waiting for lung transplantation.

Objective: Multiple gene transfer might permit modulation of concurrent biochemical pathways involved in acute lung graft rejection. We investigated whether gene cotransfection into the recipient reduces acute lung graft rejection., Methods: Brown Norway rats were used as donors, and F344 rats were used as recipients. Recipient animals were injected with saline (groups I/VI) or 1 x 10(10) pfu of adenovirus encoding beta-galactosidase (groups II/VII), transforming growth factor beta1 (groups III/VIII), interleukin 10 (groups IV/IX), or both transforming growth factor beta1 and interleukin 10 (groups V/X) into both leg muscles 2 days before transplantation (groups I-V) or at the time of harvest (groups VI-X). The Kruskal-Wallis test for rejection score and 1-way analysis of variance were used to compare groups., Results: Oxygenation was significantly improved in the cotransfected groups treated 2 days before transplantation and at the time of harvest. Rejection scores were also reduced in the cotransfected groups. In group V cotransfection suppressed endogenous interleukin 2 but not interferon gamma and tumor necrosis factor alpha., Conclusion: Recipient intramuscular cotransfection of transforming growth factor beta1 and interleukin 10 suppressed interleukin 2 expression and provided a synergistic effect that reduced acute lung graft rejection. This approach might be applied to the clinical setting because transplant recipients could be treated at the time of implantation.

Background: Tumor necrosis factor is an important mediator of lung transplant acute rejection. Soluble type I tumor necrosis factor receptor binds to tumor necrosis factor-alpha and -beta and inhibits their function. The objectives of this study were to demonstrate efficient in vivo gene transfer of a soluble type I tumor necrosis factor receptor fusion protein (sTNF-RI-Ig) and determine its effects on lung allograft acute rejection., Methods: Three groups of Fischer rats (n = 6 per group) underwent recipient intramuscular transfection 24 hours before transplantation with saline, 1 x 10(10) plaque-forming units of control adenovirus encoding beta-galactosidase, or 1 x 10(10) plaque-forming units of adenovirus encoding human sTNF-RI-Ig (Ad.sTNF-RI-Ig). One group (n = 6) received recipient intramuscular transfection with 1 x 10(10) Ad.sTNF-RI-Ig at the time of transplantation. Brown Norway donor lung grafts were stored for 5 hours before orthotopic lung transplantation. Graft function and rejection scores were assessed 5 days after transplantation. Time-dependent transgene expression in muscle, serum, and lung grafts were evaluated by using enzyme-linked immunosorbent assay of human soluble type I tumor necrosis factor receptor., Results: Recipient intramuscular transfection with 1 x 10(10) plaque-forming units of Ad.sTNF-RI-Ig significantly improved arterial oxygenation when delivered 24 hours before transplantation compared with saline, beta-galactosidase, and Ad.sTNF-RI-Ig transfection at the time of transplantation (435.8 +/- 106.6 mm Hg vs 142.3 +/- 146.3 mm Hg, 177.4 +/- 153.7 mm Hg, and 237.3 +/- 185.2 mm Hg; P =.002,.005, and.046, respectively). Transgene expression was time dependent, and there was a trend toward lower vascular rejection scores (P =.066) in the Ad.sTNF-RI-Ig group transfected 24 hours before transplantation., Conclusions: Recipient intramuscular Ad.sTNF-RI-Ig gene transfer improves allograft function in a well-established model of acute rejection. Maximum benefit was observed when transfection occurred 24 hours before transplantation.

Objective: Tumor necrosis factor is an important mediator of lung transplant ischemia-reperfusion injury, and soluble type I tumor necrosis factor receptor binds to tumor necrosis factor and works as a tumor necrosis factor inhibitor. The objectives of this study were to demonstrate that gene transfer of type I tumor necrosis factor receptor-IgG fusion protein reduces lung isograft ischemia-reperfusion injury and to compare donor endobronchial versus recipient intramuscular transfection strategies., Methods: Three donor groups of Fischer rats (n = 6/group) underwent endobronchial transfection with either saline, 2 x 10(7) plaque-forming units of control adenovirus encoding beta-galactosidase, or 2 x 10(7) plaque-forming units of adenovirus encoding type I tumor necrosis factor receptor-IgG fusion protein. Left lungs were harvested 24 hours later. Two recipient groups (n = 6/group) underwent intramuscular transfection with 2 x 10(7) plaque-forming units or 1 x 10(10) plaque-forming units of adenovirus encoding type I tumor necrosis factor receptor-IgG fusion protein 24 hours before transplantation. All donor lung grafts were stored for 18 hours before orthotopic lung transplantation. Graft function was assessed 24 hours after reperfusion. Transgene expression was evaluated by means of enzyme-linked immunosorbent assay and immunohistochemistry of type I tumor necrosis factor receptor., Results: Endobronchial transfection of donor lung grafts with 2 x 10(7) plaque-forming units of adenovirus encoding type I tumor necrosis factor receptor-IgG fusion protein significantly improved arterial oxygenation compared with the saline and beta-galactosidase donor groups (366.6 +/- 137.9 vs 138.8 +/- 159.9 and 140.6 +/- 131.4 mm Hg, P =.009 and.010, respectively). Recipient intramuscular transfection with 1 x 10(10) plaque-forming units of adenovirus encoding type I tumor necrosis factor receptor-IgG fusion protein improved lung graft oxygenation compared with that seen in the low-dose intramuscular group (2 x 10(7); 320.3 +/- 188.6 vs 143.6 +/- 20.2 mm Hg, P =.038). Type I tumor necrosis factor receptor-IgG fusion protein was expressed in endobronchial transfected grafts. In addition, intramuscular type I tumor necrosis factor receptor-IgG fusion protein expression was dose dependent., Conclusions: Donor endobronchial and recipient intramuscular adenovirus-mediated gene transfer of type I tumor necrosis factor receptor-IgG fusion protein improved experimental lung graft oxygenation after prolonged ischemia. However, donor endobronchial transfection required 500-fold less vector. Furthermore, at low vector doses, it does not create significant graft inflammation.

Objective: Because almost all pulmonary diseases are not caused by one gene, multiple gene transfection is required for current gene therapy. Adenovirus is an important gene therapy vector, but a short duration and the inability of repeated administration remain limitations. The aims of this study were to evaluate whether adenoviral vector encoding soluble tumor necrosis factor alpha receptor immunoglobulin and beta-galactosidase cotransfection prolongs gene expression and facilitates repeated vector administration to investigate the feasibility of a cotransfection strategy., Methods: F344 rats received intratracheal administration of 1 x 10(9) plaque-forming units of adenoviral vector encoding beta-galactosidase or both adenoviral vector encoding beta-galactosidase and adenoviral vector encoding soluble tumor necrosis factor alpha receptor immunoglobulin. In the expression study beta-galactosidase gene expression in the lung was examined by means of enzyme-linked immunosorbent assay on days 2, 7, 14, 28, and 56 (n = 4/day). In the repeated transfection study, soluble tumor necrosis factor alpha receptor immunoglobulin and beta-galactosidase were readministered once (7 days after the first adenovirus administration) or twice (on days 7 and 14; n = 4/day). A 2-way factorial analysis of variance was used for statistical analysis., Results: Soluble tumor necrosis factor alpha receptor immunoglobulin and beta-galactosidase cotransfection prolonged the duration of beta-galactosidase expression. However, antiadenovirus antibody production was significantly increased in the cotransfection group. In addition, there was no increase in beta-galactosidase expression after readministration of soluble tumor necrosis factor alpha receptor immunoglobulin and beta-galactosidase., Conclusion: Adenoviral vector encoding soluble tumor necrosis factor alpha receptor immunoglobulin and beta-galactosidase cotransfection prolongs beta-galactosidase expression but does not increase beta-galactosidase expression after repeated administration. These results suggest that tumor necrosis factor alpha is one of the most important factors in regulating the duration of gene expression. The cotransfection approach is feasible, but the increase of antiadenovirus antibodies might make repeated cotransfection unfeasible.