Christine L. Lau

Two Thousand Transhiatal Esophagectomies Changing Trends, Lessons Learned

Objective:“Rediscovered” in 1976, transhiatal esophagectomy (THE) has been applicable in most situations requiring esophageal resection and reconstruction. The objective of this study was to review the authors’ 30-year experience with THE and changing trends in its use. Methods:Using the authors’ prospective Esophagectomy Database, this single institution experience with THE was analyzed retrospectively. Results:Two thousand and seven THEs were performed—1063 (previously reported) between 1976 and 1998 (group I) and 944 from 1998 to 2006 (group II), 24% for benign disease, 76%, cancer. THE was possible in 98%. Stomach was the esophageal substitute in 97%. Comparing outcomes between group I and group II, statistically significant differences (P < 0.001) were observed in hospital mortality (4% vs. 1%); adenocarcinoma histology (69% vs. 86%); use of neoadjuvant chemoradiation (28% vs. 52%); mean blood loss (677 vs. 368 mL); anastomotic leak (14% vs. 9%); and discharge within 10 days (52% vs. 78%). Major complications remain infrequent: wound infection/dehiscence, 3%, atelectasis/pneumonia, 2%, intrathoracic hemorrhage, recurrent laryngeal nerve paralysis, chylothorax, and tracheal laceration, <1% each. Late functional results have been good or excellent in 73%. Aggressive preoperative conditioning, avoiding the ICU, improved pain management, and early ambulation reduce length of stay, with 50% in group II discharged within 1 week. Conclusion:THE refinements have reduced the historic morbidity and mortality of esophageal resection. This largest reported THE experience reinforces the value of consistent technique and a clinical pathway in managing these high acuity esophageal patients.

STS Database Risk Models: Predictors of Mortality and Major Morbidity for Lung Cancer Resection

BACKGROUND The aim of this study is to create models for perioperative risk of lung cancer resection using the STS GTDB (Society of Thoracic Surgeons General Thoracic Database). METHODS The STS GTDB was queried for all patients treated with resection for primary lung cancer between January 1, 2002 and June 30, 2008. Three separate multivariable risk models were constructed (mortality, major morbidity, and composite mortality or major morbidity). RESULTS There were 18,800 lung cancer resections performed at 111 participating centers. Perioperative mortality was 413 of 18,800 (2.2%). Composite major morbidity or mortality occurred in 1,612 patients (8.6%). Predictors of mortality include the following: pneumonectomy (p < 0.001), bilobectomy (p < 0.001), American Society of Anesthesiology rating (p < 0.018), Zubrod performance status (p < 0.001), renal dysfunction (p = 0.001), induction chemoradiation therapy (p = 0.01), steroids (p = 0.002), age (p < 0.001), urgent procedures (p = 0.015), male gender (p = 0.013), forced expiratory volume in one second (p < 0.001), and body mass index (p = 0.015). CONCLUSIONS Thoracic surgeons participating in the STS GTDB perform lung cancer resections with a low mortality and morbidity. The risk-adjustment models created have excellent performance characteristics and identify important predictors of mortality and major morbidity for lung cancer resections. These models may be used to inform clinical decisions and to compare risk-adjusted outcomes for quality improvement purposes.

Gastroesophageal reflux disease in lung transplant recipients

Abstract: Background: Chronic allograft dysfunction after lung transplantation contributes to poor long‐term survival. A link between gastric aspiration and post‐transplant lung dysfunction has been suggested, but little is known about the significance of gastroesophageal reflux disease (GERD) after lung transplantation.

The role of anti-Galalpha1-3Gal antibodies in acute vascular rejection and accommodation of xenografts.

BACKGROUND A major impediment to the transplanting of porcine organs into humans is the susceptibility of porcine organs to acute vascular rejection, which can destroy a vascularized xenograft over a period of hours to days. Acute vascular rejection of porcine-to-primate xenografts is thought to be triggered by binding of xenoreactive antibodies to the graft. We tested whether antibodies, binding to Galalpha1-3Gal epitopes in porcine tissue, initiate this phenomenon. METHODS AND RESULTS Specific depletion of anti-Galalpha1-3Gal antibodies from the blood of baboons, using extracorporeal perfusion of separated plasma through columns of Sepharose beads covalently linked to the antigenic trisaccharide, Galalpha1-3Galbeta1-4GlcAc, averted the development of acute vascular rejection in porcine organs transgenic for human decay-accelerating factor and CD59. More importantly, after immunodepletion was stopped and Gala1-3Gal antibodies were allowed to return, these same organs continued to function and remained pathologically normal and thus seemed to achieve a state of accommodation. CONCLUSION These results demonstrate that anti-Galalpha1-3Gal antibodies cause acute vascular rejection and suggest that depletion of these antibodies leads to accommodation of the donor cardiac xenograft and could supply an important model for additional study.

Smooth muscle phenotypic modulation is an early event in aortic aneurysms.

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 alpha-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 SM22 alpha and smooth muscle alpha-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 SM22 alpha and smooth muscle alpha-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 SM22 alpha and smooth muscle alpha-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.

Molecular biologic substaging of stage I lung cancer according to gender and histology

BACKGROUND This study is designed to assess molecular biologic substaging according to gender and histology in patients with stage I non-small cell lung cancer (NSCLC). METHODS Pathologic specimens were collected from 408 consecutive patients after complete resection for stage I NSCLC, with follow-up of at least 5 years. A panel of nine molecular markers was chosen for immunohistochemical analysis of the tumor: recessive oncogenes p53 and bcl-2, the protooncogene erbB-2, KI-67 proliferation index, retinoblastoma oncogene (Rb), epidermal growth factor receptor (EGFr), angiogenesis factor viii, sialyl-Tn antigen (STN), and CD-44. Cox proportional hazards regression analysis was used to construct a risk model for cancer-specific survival according to marker status, gender, and histologic subtype. RESULTS Among men, the only molecular marker associated with decreased cancer-specific survival is erbB-2; among women, there are four markers: p53, Rb, CD-44, and factor viii. Among patients with squamous cell carcinoma, the only molecular marker associated with decreased cancer-specific survival is erbB-2; among patients with adenocarcinoma (AC), there are three markers: p53, CD-44, and factor viii. Multivariable analysis of interactions among molecular markers, gender, and histology demonstrates two important relationships (hazard ratio): p53+/women (2.269) and CD-44+/AC (2.266). CONCLUSIONS Molecular biologic substaging of patients with stage I NSCLC demonstrates differential cancer-specific survival according to marker expression, gender, and histologic subtype.

Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients

BACKGROUND Panel-reactive antibody (PRA) is used to estimate the degree of humoral sensitization in the recipient before transplantation. Although pretransplant sensitization is associated with increased complications in other solid organ transplant recipients, less is known about the outcome of sensitized lung transplant recipients. Therefore, we sought to determine the impact of elevated pretransplant PRA on clinical outcomes after lung transplantation. METHODS The records of the first 200 lung transplant operations performed at Duke University Medical Center were reviewed. The outcomes of sensitized patients, PRA greater than 10% before transplantation (n = 18), were compared with the outcomes of nonsensitized patients. RESULTS Sensitized patients experienced a significantly greater number of median ventilator days posttransplant (9 +/- 8) as compared with nonsensitized recipients (1 +/- 11; p = 0.0008). There were no significant differences between the number of episodes of acute rejection; however, there was a significantly increased incidence of bronchiolitis obliterans syndrome occurring in untreated sensitized recipients (56%) versus nonsensitized (23%; p = 0.044). In addition, there was a trend towards decreased survival in the sensitized recipients, with a 2-year survival of 58% in sensitized recipients as compared with 73% in the nonsensitized patients (p = 0.31). CONCLUSIONS Sensitized lung transplant recipients experience more acute and chronic complications after transplantation. These patients probably warrant alternative management strategies.

Size matters: a comparison of T1 and T2 peripheral non-small-cell lung cancers treated with stereotactic body radiation therapy (SBRT).

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.

Natural Killer T Cell–derived IL-17 Mediates Lung Ischemia–Reperfusion Injury

RATIONALE We recently implicated a role for CD4(+) T cells and demonstrated elevated IL-17A expression in lung ischemia-reperfusion (IR) injury. However, identification of the specific subset of CD4(+) T cells and their mechanistic role in IR injury remains unknown. OBJECTIVES We tested the hypothesis that invariant natural killer T (iNKT) cells mediate lung IR injury via IL-17A signaling. METHODS Mice underwent lung IR via left hilar ligation. Pulmonary function was measured using an isolated lung system. Lung injury was assessed by measuring edema (wet/dry weight) and vascular permeability (Evans blue dye). Inflammation was assessed by measuring proinflammatory cytokines in lungs, and neutrophil infiltration was measured by immunohistochemistry and myeloperoxidase levels. MEASUREMENTS AND MAIN RESULTS Pulmonary dysfunction (increased airway resistance and pulmonary artery pressure and decreased pulmonary compliance), injury (edema, vascular permeability), and inflammation (elevated IL-17A; IL-6; tumor necrosis factor-α; monocyte chemotactic protein-1; keratinocyte-derived chemokine; regulated upon activation, normal T-cell expressed and secreted; and neutrophil infiltration) after IR were attenuated in IL-17A(-/-) and Rag-1(-/-) mice. Anti-IL-17A antibody attenuated lung dysfunction in wild-type mice after IR. Reconstitution of Rag-1(-/-) mice with wild-type, but not IL-17A(-/-), CD4(+) T cells restored lung dysfunction, injury, and inflammation after IR. Lung dysfunction, injury, IL-17A expression, and neutrophil infiltration were attenuated in Jα18(-/-) mice after IR, all of which were restored by reconstitution with wild-type, but not IL-17A(-/-), iNKT cells. Flow cytometry and enzyme-linked immunosorbent spot assay confirmed IL-17A production by iNKT cells after IR. CONCLUSIONS These results demonstrate that CD4(+) iNKT cells play a pivotal role in initiating lung injury, inflammation, and neutrophil recruitment after IR via an IL-17A-dependent mechanism.

Analysis of Cervical Esophagogastric Anastomotic Leaks After Transhiatal Esophagectomy: Risk Factors, Presentation, and Detection

BACKGROUND Transhiatal esophagectomy with cervical esophagogastric anastomosis is a common approach in patients requiring esophagectomy. Factors for developing cervical esophagogastric anastomosis leaks (CEGAL), their presentation, and the value of a routine postoperative screening barium swallow in detecting CEGALs and other complications were analyzed. METHODS This single-institution retrospective study used medical records and an esophagectomy database to assess results in 1,133 patients who underwent transhiatal esophagectomy and a cervical esophagogastric anastomosis, 241 for benign disease and 892 for cancer, between January 1996 and December 2006. RESULTS Esophagectomy patients who experienced CEGALs included 127 (14.2%) with cancer and 23 (9.5%) with benign disease. Logistic regression analysis identified increasing number of preoperative comorbidities (p < 0.001), active smoking history (p = 0.044), and postoperative arrhythmia (p = 0.002) as risk factors for CEGALs, and a side-to-side stapled cervical esophagogastric anastomosis compared with a manually sewn one as protective (p < 0.001). For cancer patients, higher pathologic stage disease (p = 0.050) was a risk factor for CEGALs. For patients with benign disease, a higher number of prior esophagogastric operations (p = 0.007) is a risk factor for CEGALs. Of the 90.7% of CEGALs that occurred on or before postoperative day 10, cervical wound drainage (63.3%) was the most common presenting symptom. Screening barium swallow identified postoperative complications and influenced outcome in 39 patients (3.8%). CONCLUSIONS Higher number of preoperative comorbidities, advanced pathologic stage, postoperative arrhythmia, an increased number of prior esophagogastric surgeries, and active smoking history are risk factors for developing CEGAL, and a side-to-side stapled cervical esophagogastric anastomosis is protective. Screening barium swallow identifies few postoperative complications, but provides quality control.