Benjamin D. Kozower

Immunotargeting of catalase to the pulmonary endothelium alleviates oxidative stress and reduces acute lung transplantation injury

Vascular immunotargeting may facilitate the rapid and specific delivery of therapeutic agents to endothelial cells. We investigated whether targeting of an antioxidant enzyme, catalase, to the pulmonary endothelium alleviates oxidative stress in an in vivo model of lung transplantation. Intravenously injected enzymes, conjugated with an antibody to platelet-endothelial cell adhesion molecule-1, accumulate in the pulmonary vasculature and retain their activity during prolonged cold storage and transplantation. Immunotargeting of catalase to donor rats augments the antioxidant capacity of the pulmonary endothelium, reduces oxidative stress, ameliorates ischemia-reperfusion injury, prolongs the acceptable cold ischemia period of lung grafts, and improves the function of transplanted lung grafts. These findings validate the therapeutic potential of vascular immunotargeting as a drug delivery strategy to reduce endothelial injury. Potential applications of this strategy include improving the outcome of clinical lung transplantation and treating a wide variety of endothelial disorders.

Intramuscular Gene Transfer of Interleukin‐10 Reduces Neutrophil Recruitment and Ameliorates Lung Graft Ischemia‐Reperfusion Injury

Interleukin‐10 (IL‐10) has potent anti‐inflammatory properties but its direct effects on neutrophil trafficking in lung transplant ischemia‐reperfusion (I/R) injury are unknown. This study was performed to determine if recipient intramuscular IL‐10 gene transfer reduces neutrophil infiltration in lung isografts and ameliorates I/R injury. Twenty‐four hours before transplantation, recipient rodents received intramuscular injection with 1u2003×u20031010 plaque‐forming units (pfu) adenovirus encoding human IL‐10 (hIL‐10), 1u2003×u20031010 pfu adenovirus control encoding β‐galactosidase, or saline. Gene expression in muscle and plasma was confirmed. Lung grafts were harvested, stored at 4u2003°C for 18u2003h, and assessed 24u2003h after transplantation. Peak muscle and plasma expression of hIL‐10 was achieved 24u2003h after gene transfer and returned to baseline by 7u2003days (p <u200a0.05 vs. controls). Gene transfer of hIL‐10 reduced neutrophil sequestration and emigration in lung grafts as measured by morphometry and myeloperoxidase activity (p <u200a0.03 vs. controls). Furthermore, hIL‐10 improved graft oxygenation and reduced lung edema (p <u200a0.01 vs. controls). Intramuscular gene transfer of hIL‐10 releases hIL‐10 protein into plasma and reduces neutrophil sequestration and emigration in lung isografts. This is associated with a reduction in I/R injury with improved isograft oxygenation and reduced tissue edema. Intramuscular gene transfer may be a useful strategy to reduce clinical I/R injury.

Tumor necrosis factor inhibitor gene transfer ameliorates lung graft ischemia-reperfusion injury.

OBJECTIVEnTumor 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.nnnMETHODSnThree 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.nnnRESULTSnEndobronchial 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.nnnCONCLUSIONSnDonor 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.

Treatment of stage I non–small cell lung cancer: What's trending?

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.

The American Association for Thoracic Surgery consensus guidelines for the management of empyema.

Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e2 Methods of Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e2 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e3 Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . .e3 Reasoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e3 Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e4 Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . .e4 Reasoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e4 Chest X-ray . . . . . . . . . . . . . . . . . . . . . . . . . . . .e4 Pleural US . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e4

Prospective study of giant paraesophageal hernia repair with 1-year follow-up

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.

The Society of Thoracic Surgeons National Database 2017 Annual Report

The Society of Thoracic Surgeons (STS) National Database has three major component databases: the STSxa0Adult Cardiac Surgery Database (ACSD), the STS Congenital Heart Surgery Database (CHSD), and the STS General Thoracic Surgery Database (GTSD). Beginning in January 2016, The Annals of Thoracic Surgery began publishing a monthly series of scholarly articles on outcomes analysis, quality improvement, and patient safety. This article summarizes the status of the STS National Database as of October 2017 and summarizes the articles about the STS National Database that appeared in The Annals of Thoracic Surgery 2017 series Outcomes Analysis, Quality Improvement, and Patient Safety.

The Society of Thoracic Surgeons Composite Score for Evaluating Esophagectomy for Esophageal Cancer

BACKGROUNDnThe Society of Thoracic Surgeons (STS) has developed composite quality measures for cardiac surgical procedures and lobectomy for lung cancer. This study sought to develop a composite measure for esophagectomy for esophageal cancer.nnnMETHODSnThe STS esophagectomy composite score is derived from two risk-adjusted outcomes: mortality and major complications. General Thoracic Surgery Database data were included from 2012 to 2014, and 95% Bayesian credible intervals were established to determine star ratings. STS participants were compared with the National Inpatient Sample as a national benchmark (including non-STS participants).nnnRESULTSnThe study population included 4,321 patients who underwent esophagectomy from 167 participating centers. The operative mortality rate was 3.1% (Nxa0= 135), and the major complication rate was 33.1% (Nxa0= 1,429). Of the 167 participants, 70 reported an average yearly volume of five or more esophagectomies during the study period. With this threshold, reliability for the composite score was 0.58 (95% credible interval, 0.41 to 0.72). Of these 70 participants, 5 (7.1%) were three star, 63 (90.0%) were two star, and 2 (2.9%) were one star. A majority of STS participants, 58.1% (Nxa0= 97), did not have sufficient volume to receive a reliable composite score. Benchmarked to the 2012 National Inpatient Sample cohort, STS General Thoracic Surgery Database participants have comparable discharge mortality rates and shorter postoperative lengths of stay.nnnCONCLUSIONSnSTS has developed a quality measure for esophageal cancer surgical procedures based on a composite score of risk-adjusted operative mortality rates and major complications. The composite rating for esophagectomy has good reliability for programs performing an average of five procedures annually, although almost 60% of participants are not eligible for a star rating because of lower procedure volumes.

Volume-Outcome Relationships in Thoracic Surgery

Most thoracic surgery studies indicate that hospital and surgeon procedure volume are inversely associated with mortality. However, controversy exists regarding the strength and validity of this volume-outcome association. Because thresholds of procedure volume are used to recommend the regionalization of care, investigation of the volume-outcome relationship is imperative. This article examines the methodology used in the volume-outcome relationship literature and highlights important areas of concern. Careful examination of the literature demonstrates that lung and esophageal cancer resection volume is not strongly associated with mortality and should not be used as a proxy measure for quality.

Adenovirus encoding soluble tumor necrosis factor α receptor immunoglobulin prolongs gene expression of a cotransfected reporter gene in rat lung

OBJECTIVEnBecause 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.nnnMETHODSnF344 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.nnnRESULTSnSoluble 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.nnnCONCLUSIONnAdenoviral 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.