John C. Kucharczuk

Predictors of major morbidity and mortality after esophagectomy for esophageal cancer: A Society of Thoracic Surgeons General Thoracic Surgery Database risk adjustment model

OBJECTIVE To create a model for perioperative risk of esophagectomy for cancer using the Society of Thoracic Surgeons General Thoracic Database. METHODS The Society of Thoracic Surgeons General Thoracic Database was queried for all patients treated with esophagectomy for esophageal cancer between January 2002 and December 2007. A multivariable risk model for mortality and major morbidity was constructed. RESULTS There were 2315 esophagectomies performed by 73 participating centers. Hospital mortality was 63/2315 (2.7%). Major morbidity (defined as reoperation for bleeding [n = 12], anastomotic leak [n = 261], pneumonia [n = 188], reintubation [n = 227], ventilation beyond 48 hours [n = 71], or death [n = 63]) occurred in 553 patients (24%). Preoperative spirometry was obtained in 923/2315 (40%) of patients. A forced expiratory volume in 1 second < 60% of predicted was associated with major morbidity (P = .0044). Important predictors of major morbidity are: age 75 versus 55 (P = .005), black race (P = .08), congestive heart failure (P = .015), coronary artery disease (P = .017), peripheral vascular disease (P = .009), hypertension (P = .029), insulin-dependent diabetes (P = .009), American Society of Anesthesiology rating (P = .001), smoking status (P = .022), and steroid use (P = .026). A strong volume performance relationship was not observed for the composite measure of morbidity and mortality in this patient cohort. CONCLUSIONS Thoracic surgeons participating in the Society of Thoracic Surgeons General Thoracic Database perform esophagectomy with a low mortality. We identified important predictors of major morbidity and mortality after esophagectomy for esophageal cancer. Volume alone is an inadequate proxy for quality assessment after esophagectomy.

International consensus on standardization of data collection for complications associated with esophagectomy: Esophagectomy Complications Consensus Group (ECCG)

INTRODUCTION Perioperative complications influence long- and short-term outcomes after esophagectomy. The absence of a standardized system for defining and recording complications and quality measures after esophageal resection has meant that there is wide variation in evaluating their impact on these outcomes. METHODS The Esophageal Complications Consensus Group comprised 21 high-volume esophageal surgeons from 14 countries, supported by all the major thoracic and upper gastrointestinal professional societies. Delphi surveys and group meetings were used to achieve a consensus on standardized methods for defining complications and quality measures that could be collected in institutional databases and national audits. RESULTS A standardized list of complications was created to provide a template for recording individual complications associated with esophagectomy. Where possible, these were linked to preexisting international definitions. A Delphi survey facilitated production of specific definitions for anastomotic leak, conduit necrosis, chyle leak, and recurrent nerve palsy. An additional Delphi survey documented consensus regarding critical quality parameters recommended for routine inclusion in databases. These quality parameters were documentation on mortality, comorbidities, completeness of data collection, blood transfusion, grading of complication severity, changes in level of care, discharge location, and readmission rates. CONCLUSIONS The proposed system for defining and recording perioperative complications associated with esophagectomy provides an infrastructure to standardize international data collection and facilitate future comparative studies and quality improvement projects.

Nonoperative thoracic duct embolization for traumatic thoracic duct leak: Experience in 109 patients

OBJECTIVE To demonstrate the efficacy of a minimally invasive, nonoperative, catheter-based approach to the treatment of traumatic chyle leak. METHODS A retrospective review of 109 patients was conducted to assess the efficacy of thoracic duct embolization or interruption for the treatment of high-output chyle leak caused by injury to the thoracic duct. RESULTS A total of 106 patients presented with chylothorax, 1 patient presented with chylopericardium, and 2 patients presented with cervical lymphocele. Twenty patients (18%) had previous failed thoracic duct ligation. In 108 of 109 patients, a lymphangiogram was successful. Catheterization of the thoracic duct was achieved in 73 patients (67%). In 71 of these 73 patients, embolization of the thoracic duct was performed. Endovascular coils or liquid embolic agent was used to occlude the thoracic duct. In 18 of 33 cases of unsuccessful catheterization, thoracic duct needle interruption was attempted below the diaphragm. Resolution of the chyle leak was observed in 64 of 71 patients (90%) post-embolization. Needle interruption of the thoracic duct was successful in 13 of 18 patients (72%). In 17 of the 20 patients who had previous attempts at thoracic duct ligation, embolization or interruption was attempted and successful in 15 (88%). The overall success rate for the entire series was 71% (77/109). There were 3 (3%) minor complications. CONCLUSION Catheter embolization or needle interruption of the thoracic duct is safe, feasible, and successful in eliminating a high-output chyle leak in the majority (71%) of patients. This minimally invasive, although technically challenging, procedure should be the initial approach for the treatment of a traumatic chylothorax.

Gene Expression Profiles in Peripheral Blood Mononuclear Cells Can Distinguish Patients with Non–Small Cell Lung Cancer from Patients with Nonmalignant Lung Disease

Early diagnosis of lung cancer followed by surgery presently is the most effective treatment for non-small cell lung cancer (NSCLC). An accurate, minimally invasive test that could detect early disease would permit timely intervention and potentially reduce mortality. Recent studies have shown that the peripheral blood can carry information related to the presence of disease, including prognostic information and information on therapeutic response. We have analyzed gene expression in peripheral blood mononuclear cell samples including 137 patients with NSCLC tumors and 91 patient controls with nonmalignant lung conditions, including histologically diagnosed benign nodules. Subjects were primarily smokers and former smokers. We have identified a 29-gene signature that separates these two patient classes with 86% accuracy (91% sensitivity, 80% specificity). Accuracy in an independent validation set, including samples from a new location, was 78% (sensitivity of 76% and specificity of 82%). An analysis of this NSCLC gene signature in 18 NSCLCs taken presurgery, with matched samples from 2 to 5 months postsurgery, showed that in 78% of cases, the signature was reduced postsurgery and disappeared entirely in 33%. Our results show the feasibility of using peripheral blood gene expression signatures to identify early-stage NSCLC in at-risk populations.

Transcervical Thymectomy for Myasthenia Gravis Achieves Results Comparable to Thymectomy by Sternotomy

BACKGROUND It remains controversial whether transcervical thymectomy offers results equivalent to thymectomy by way of a median sternotomy in the treatment of myasthenia gravis. Furthermore, preoperative prognostic factors have not been clearly defined. METHODS This study is a retrospective chart review and interview of 78 patients completing transcervical thymectomy for myasthenia gravis between 1992 and 1999. RESULTS There were 24 men and 54 women. Mean age was 40 years (range, 13 to 78 years). Twelve patients were in Osserman class 1, 25 in class 2, 30 in class 3, and 11 in class 4 (mean, 2.5). There was no perioperative mortality and 6 (7.7%) morbidities. Mean length of stay was 1.5 days and mean follow-up, 54.6 months. The crude cumulative complete remission (asymptomatic off medications for 6 months) rate was 39.7% (n = 31). Only 8 patients (10.3%) failed to improve after transcervical thymectomy. Kaplan-Meier estimates of complete remission were 31% and 43% at 2 and 5 years, respectively. Eight patients with thymoma had a 5-year estimated complete remission rate of 75% in contrast to 43% in 38 patients with thymic hyperplasia and 36% in 32 patients with neither thymoma nor hyperplasia (p = 0.01). Twelve patients with ocular myasthenia had a 5-year estimated complete remission rate of 57%, whereas patients with mild-to-moderate (n = 55) or severe (n = 11) generalized symptoms had 5-year complete remission rates of 43% and 30%, respectively (p = 0.21). CONCLUSIONS Overall, extended transcervical thymectomy offers results that are comparable to those published for the transsternal procedure. Patients with milder disease (including isolated ocular disease) and taking no preoperative immunosuppressive agents appear to experience higher remission rates. In contrast to previous studies, we also find that small thymomas predict better responses to thymectomy.

MicroRNA Expression Profiles of Whole Blood in Lung Adenocarcinoma

The association of lung cancer with changes in microRNAs in plasma shown in multiple studies suggests a utility for circulating microRNA biomarkers in non-invasive detection of the disease. We examined if presence of lung cancer is reflected in whole blood microRNA expression as well, possibly because of a systemic response. Locked nucleic acid microarrays were used to quantify the global expression of microRNAs in whole blood of 22 patients with lung adenocarcinoma and 23 controls, ten of whom had a radiographically detected non-cancerous lung nodule and the other 13 were at high risk for developing lung cancer because of a smoking history of >20 pack-years. Cases and controls differed significantly for age with a mean difference of 10.7 years, but not for gender, race, smoking history, blood hemoglobin, platelet count, or white blood cell count. Of 1282 quantified human microRNAs, 395 (31%) were identified as expressed in the study’s subjects, with 96 (24%) differentially expressed between cases and controls. Classification analyses of microRNA expression data were performed using linear kernel support vector machines (SVM) and top-scoring pairs (TSP) methods, and classifiers to identify presence of lung adenocarcinoma were internally cross-validated. In leave-one-out cross-validation, the TSP classifiers had sensitivity and specificity of 91% and 100%, respectively. The values with SVM were both 91%. In a Monte Carlo cross-validation, average sensitivity and specificity values were 86% and 97%, respectively, with TSP, and 88% and 89%, respectively, with SVM. MicroRNAs miR-190b, miR-630, miR-942, and miR-1284 were the most frequent constituents of the classifiers generated during the analyses. These results suggest that whole blood microRNA expression profiles can be used to distinguish lung cancer cases from clinically relevant controls. Further studies are needed to validate this observation, including in non-adenocarcinomatous lung cancers, and to clarify upon the confounding effect of age.

Endobronchial Valve Treatment for Prolonged Air Leaks of the Lung: A Case Series

PURPOSE An endobronchial valve developed for treatment of severe emphysema has characteristics favorable for bronchoscopic treatment of air leaks. We present the results of a consecutive case series treating complex alveolopleural fistula with valves. DESCRIPTION Patients with air leaks that persisted after treatment gave consent and compassionate use approval was obtained. Bronchoscopy with balloon occlusion was used to identify the airways to be treated. IBV Valves (Spiration, Redmond, WA) were placed after airway measurement. EVALUATION During a 15-month period, 8 valve placement procedures were performed in 7 patients and all had improvement in the air leak. The median duration of air leakage was 4 weeks before and 1 day after treatment, with a mean of 4.5 days. Discharge within 2 to 3 days of the procedure occurred in 57% of the patients. A median of 3.5 valves (mode, 2.4) were used, and all valve removals were successful. There were no procedural or valve-related complications. CONCLUSIONS Removable endobronchial valves appear to be a safe and effective intervention for prolonged air leaks.

A 10-gene classifier for distinguishing head and neck squamous cell carcinoma and lung squamous cell carcinoma.

Purpose: The risk of developing metastatic squamous cell carcinoma for patients with head and neck squamous cell carcinoma (HNSCC) is very high. Because these patients are often heavy tobacco users, they are also at risk for developing a second primary cancer, with squamous cell carcinoma of the lung (LSCC) being the most common. The distinction between a lung metastasis and a primary LSCC is currently based on certain clinical and histologic criteria, although the accuracy of this approach remains in question. Experimental Design: Gene expression patterns derived from 28 patients with HNSCC or LSCC from a single center were analyzed using penalized discriminant analysis. Validation was done on previously published data for 134 total subjects from four independent Affymetrix data sets. Results: We identified a panel of 10 genes (CXCL13, COL6A2, SFTPB, KRT14, TSPYL5, TMP3, KLK10, MMP1, GAS1, and MYH2) that accurately distinguished these two tumor types. This 10-gene classifier was validated on 122 subjects derived from four independent data sets and an average accuracy of 96% was shown. Gene expression values were validated by quantitative reverse transcription-PCR derived on 12 independent samples (seven HNSCC and five LSCC). The 10-gene classifier was also used to determine the site of origin of 12 lung lesions from patients with prior HNSCC. Conclusions: The results suggest that penalized discriminant analysis using these 10 genes will be highly accurate in determining the origin of squamous cell carcinomas in the lungs of patients with previous head and neck malignancies.

A Phase I Trial of the HIV Protease Inhibitor Nelfinavir with Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer A Report of Toxicities and Clinical Response

Background: The objective of this phase I trial was to determine dose-limiting toxicities (DLT) and the maximally tolerated dose of the radiosensitizer Nelfinavir in combination with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC). Methods: Nelfinavir (dose level 1: 625 mg orally [PO] twice a day; dose level 2: 1250 mg PO twice a day) was administered for 7 to 14 days before and concurrently with concurrent chemoradiotherapy to patients with biopsy confirmed IIIA or IIIB unresectable NSCLC. Five patients were treated at dose level 1; eight patients were treated at dose level 2. Patients were treated with concurrent chemoradiotherapy to a dose of 66.6 Gy. DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis. Results: Sixteen patients were enrolled and 13 patients received at least one dose of nelfinavir. Twelve patients were treated with nelfinavir and concurrent chemoradiotherapy. No DLTs have been observed at either dose level. The maximum tolerated dose of nelfinavir was therefore 1250 mg PO twice a day. Six patients experienced grade 4 leukopenia. One patient experienced grade 4 thromobcytopenia. Median follow-up for all 12 response-evaluable patients was 31.6 months and for survivors is 23.5 months. Nine of the 12 patients had evaluable posttreatment positron emission tomography/computed tomography with metabolic response as follows: overall response: 9/9 (100%); complete response: 5/9 (56%); and partial response: 4/9 (44%). Conclusion: Nelfinavir administered with concurrent chemoradiotherapy is associated with acceptable toxicity in stage IIIA/IIIB NSCLC. The metabolic response and tumor response data suggest that nelfinavir has promising activity in this disease.

Improved Survival after Pulmonary Metastasectomy for Soft Tissue Sarcoma

Introduction:Survival after pulmonary metastasectomy for soft tissue sarcoma (STS) has been lower than in osteosarcoma (14–40% versus 40–50%). With improved patient selection criteria and advanced chemotherapy agents, we hypothesized that survival after metastasectomy for STS has improved in recent years. Methods:Retrospective study of 48 patients undergoing pulmonary metastasectomy for STS between 1995 and 2007. Potential predictors of overall survival and disease-free survival (DFS) were examined using the log-rank test or Cox regression. Multivariate analysis was conducted using Cox regression. Results:Overall survival after initial metastasectomy was 67% and 52% at 3 and 5 years, respectively; DFS was 17% and 10% at 3 and 5 years. Univariate analysis indicated that ≤2 pulmonary metastases (p = 0.03), diameter of largest metastasis ≤2 cm (p = 0.09), and the absence of extrapulmonary metastases (p = 0.10) were associated with longer overall survival. Absence of extrapulmonary metastases (p = 0.07) and smaller size of the largest pulmonary metastasis (p = 0.06) were associated with longer DFS. Before 2001, 46.7% of patients received adjuvant chemotherapy versus 72.7% after (p = 0.10). Neither use of chemotherapy nor chemotherapy type was related to overall survival or DFS. Conclusion:Five-year overall survival is substantially higher after pulmonary metastasectomy for STS in our study relative to previously published results (52% versus 14–40%). This improvement does not seem to be the result of greater use of, or newer, chemotherapeutic regimens. Among potential explanations, improved patient selection is the most likely factor.