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Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m2 IV day 1, or 25 mg/m2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S ( P = .212). Conclusion This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.

The literature regarding laparoscopic hiatal hernia repair is difficult to interpret because of inconsistencies in describing hernia characteristics and outcome measures. This study was performed to evaluate risk factors for an unsatisfactory outcome after repair using objective definitions of hernia size and a clinically relevant outcome instrument. A retrospective review of a prospectively maintained database was conducted over a seven-year period. Data collected included patient demographics and hernia-related variables. Outcomes were defined using a validated quality of life (QOL) instrument. Postoperatively, the mean total QOL score decreased from 22.9 to 5.8 (P < 0.001). In all, 13.8 per cent of patients had unsatisfactory QOL scores postoperatively. Multivariate analysis showed that high gastroesophageal (GE) junction position (P = 0.03) and female gender (P = 0.02) were the only significant factors associated with an unsatisfactory postoperative QOL. Laparoscopic hiatal hernia repair significantly improves QOL. With respect to predicting clinically relevant outcomes, hernias are best characterized by the position of the GE junction. Females with high GE junction position are at the highest risk for an unsatisfactory outcome.

IntroductionThymic epithelial tumors (TETs) are associated with paraneoplastic/autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs.MethodsThe International Thymic Malignancy Interest Group retrospective database was examined to determine (1) baseline and treatment characteristics associated with PN/AI syndromes and (2) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis.ResultsA total of 6670 patients with known PN/AI syndrome status from 1951 to 2012 were identified. PN/AI syndromes were associated with younger age, female sex, thymoma histologic type, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the group with a PN/AI syndrome than in the group without a PN/AI syndrome (10-year CIR 17.3% versus 21.2%, respectively [p= 0.0003]). The OS was improved in the group with a PN/AI syndrome compared to the group without a PN/AI syndrome (median OS 21.6 years versus 17.0 years, respectively [hazard ratio= 0.63, 95% confidence interval: 0.54-0.74, p < 0.0001]). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor.DiscussionPreviously, there have been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest data set in the world for TETs, PN/AI syndromes were associated with favorable features (i.e., earlier stage and complete resection status) but were not an independent prognostic factor for patients with TETs.

Objective:To compare long-term survival rates of patients with first, primary, clinical stage IA nonsmall cell lung cancer from a large cohort undergoing computed tomography screening with and without mediastinal lymph node resection (MLNR) under an Institutional Review Board-approved common protoco

Introduction Thymic carcinomas are rare epithelial malignancies with limited data to guide management. Methods To identify areas of agreement and variability in current clinical practice, a 16-question electronic survey was given to members of the International Thymic Malignancy Interest Group (ITMIG). Areas of controversy were discussed with the Thymic Carcinoma Working Group and consensus was achieved, as described. Results A total of 100 ITMIG members responded. There was general agreement regarding the role for multimodality therapy with definitive surgical resection in physically fit patients with advanced but resectable disease. Areas of controversy included the need for histologic confirmation before surgery, the role of adjuvant therapy, the optimal first-line chemotherapy regimen, and the recommended treatment course for marginally resectable disease with invasion into the great vessels, pericardium, and lungs. Conclusions The results of the questionnaire provide a description of the management of thymic carcinoma by 100 ITMIG members with a specific interest or expertise in thymic malignancies. Although there was agreement in some areas, clinical practice appears to vary significantly. There is a great need for collaborative research to identify optimal evaluation and treatment strategies. Given the need for multimodality therapy in many cases, a multidisciplinary discussion of the management of patients with thymic carcinoma is critical.

Mediastinal lesions are uncommon; studies on their distribution are, in general, small and from a single institution. Furthermore, these studies are usually based on pathology or surgical databases and, therefore, miss many lesions that did not undergo biopsy or resection. Our aim was to identify the distribution of lesions in the mediastinum in a large international, multi-institutional cohort.At each participating institution, a standardized retrospective radiology database search was performed for interpretations of computed tomography, positron emission tomography-computed tomography, and magnetic resonance imaging scans including any of the following terms: "mediastinal nodule," "mediastinal lesion," "mediastinal mass," or "mediastinal abnormality" (2011-2014). Standardized data were collected. Statistical analysis was performed.Among 3308 cases, thymomas (27.8%), benign mediastinal cysts (20.0%), and lymphomas (16.1%) were most common. The distribution of lesions varied among mediastinal compartments; thymomas (38.3%), benign cysts (16.8%), and neurogenic tumors (53.9%) were the most common lesions in the prevascular, visceral, and paravertebral mediastinum, respectively (p0.001). Mediastinal compartment was associated with age; patients with paravertebral lesions were the youngest (p0.0001). Mediastinal lesions differed by continent or country, with benign cysts being the most common mediastinal lesions in the People's Republic of China, thymomas in Europe, and lymphomas in North America and Israel (p0.001). Benign cysts, thymic carcinomas, and metastases were more often seen in larger hospitals, whereas lymphomas and thymic hyperplasia occurred more often in smaller hospitals (p 0.01).Our study confirmed that the spectrum and frequency of mediastinal lesions depend on mediastinal compartment and age. This information provides helpful demographic data and is important when considering the differential diagnosis of a mediastinal lesion.

Objectives The aim of this study was to determine whether postoperative radiation therapy (PORT) is associated with an overall survival (OS) benefit in patients with completely resected Masaoka or Masaoka-Koga stage II and III thymoma. Methods All patients with completely resected (R0) stage II or III thymoma were identified in a large database of the International Thymic Malignancy Interest Group. Clinical, pathologic, treatment, and follow-up information were extracted. OS was the primary end point. A univariate analysis using the log-rank test was performed, and a multivariate Cox model was created to identify factors associated with OS. Results Of 1263 patients meeting the selection criteria, 870 (69%) had stage II thymoma. The WHO histologic subtype was A/AB in 360 patients (30%) and B1/B2/B3 in 827 (70%). PORT was given to 55% of patients (n = 689), 15% (n = 180) received chemotherapy, and 10% (n = 122) received both. The 5- and 10-year OS rates for patients having undergone an operation plus PORT were 95% and 86%, respectively, compared with 90% and 79% for patients receiving an operation alone (p = 0.002). This OS benefit remained significant when patients with stage II (p = 0.02) and stage III thymoma (p = 0.0005) were analyzed separately. On multivariate analysis, earlier stage, younger age, absence of paraneoplastic syndrome, and PORT were significantly associated with improved OS. Conclusions We observed an OS benefit with the use of PORT in completely resected stage II and III thymoma. In the absence of a randomized trial, this represents the most comprehensive analysis of individual patient data and strong evidence in favor of PORT in this patient population.

The literature regarding laparoscopic hiatal hernia repair is difficult to interpret because of inconsistencies in describing hernia characteristics and outcome measures. This study was performed to evaluate risk factors for an unsatisfactory outcome after repair using objective definitions of hernia size and a clinically relevant outcome instrument. A retrospective review of a prospectively maintained database was conducted over a seven-year period. Data collected included patient demographics and hernia-related variables. Outcomes were defined using a validated quality of life (QOL) instrument. Postoperatively, the mean total QOL score decreased from 22.9 to 5.8 (P0.001). In all, 13.8 per cent of patients had unsatisfactory QOL scores postoperatively. Multivariate analysis showed that high gastroesophageal (GE) junction position (P = 0.03) and female gender (P = 0.02) were the only significant factors associated with an unsatisfactory postoperative QOL. Laparoscopic hiatal hernia repair significantly improves QOL. With respect to predicting clinically relevant outcomes, hernias are best characterized by the position of the GE junction. Females with high GE junction position are at the highest risk for an unsatisfactory outcome.

Background Recent multiinstitutional published data have demonstrated increased pathologic nodal upstaging by robotic lobectomy compared with historical video-assisted thoracic surgery (VATS) lobectomy data. To eliminate potential variability from multiple surgical techniques, we compared the rate of nodal upstaging at a single institution where robotic and VATS lobectomy are both performed. Methods We retrospectively reviewed clinically node-negative patients with lung cancer undergoing VATS or robotic lobectomy. Clinical data were recorded in concordance with The Society of Thoracic Surgeons database elements. The rates of pathologic nodal upstaging as well as disease-free and overall survival were calculated. Results A total of 211 patients underwent anatomic lobectomy by VATS (n = 158) or robotics (n = 53) from 2009 to 2014. The two groups were statistically similar in their clinical stage, tumor size, location, and histologic evaluation. Within the VATS group, 24 patients experienced nodal upstaging (15.2%), with 13 patients having pN1 disease, and 11 patients having pN2 disease. The robotics group contained 7 patients (13.2%) with nodal upstaging, with 5 patients exhibiting pN1 disease and 2 patients with pN2 disease. When VATS and robotics were compared, there was no significant difference in pathologic upstaging ( p = 0.72), 2-year overall survival (88% vs 95%, respectively; p = 0.40), or 2-year disease-free survival (83% vs 93%, respectively; p = 0.48). Conclusions In this comparison of robotic and VATS lobectomy for clinically node-negative lung cancer that was managed with consistent surgical technique and pathologic evaluation, the rate of nodal upstaging achieved by robotics appears similar to VATS. In addition, there were no appreciable differences in disease-free or overall survival.

Cancer testis antigens (CTAs) are widely expressed in tumor tissues, circulating tumor cells (CTCs) and in cancer derived exosomes that are frequently engulfed by lymphoid cells. To determine whether tumor derived CTA mRNAs could be detected in RNA from purified peripheral blood mononuclear cells (PBMC) of non-small cell lung cancer (NSCLC) patients, we assayed for the expression of 116 CTAs in PBMC RNA in a discovery set and identified AKAP4 as a potential NSCLC biomarker. We validated AKAP4 as a highly accurate biomarker in a cohort of 264 NSCLCs and 135 controls from 2 different sites including a subset of controls with high risk lung nodules. When all (264) lung cancers were compared with all (135) controls the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers are compared with all controls the AUC is 0.9795 and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules, a comparison of significant clinical importance, the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage, but independent of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer.

Objectives To determine if there are advantages to transitioning to robotics by a surgeon who is already proficient in performing video-assisted thoracic surgical (VATS) lobectomy. Methods A single surgeon proficient in VATS lobectomy initiated a robotic lobectomy program, and a retrospective review was conducted of his patients undergoing minimally invasive lobectomy (robotics or VATS) for lung cancer between 2011 and 2012. Data collected included patient/tumor characteristics, morbidity, mortality, operative times, and length of hospital stay. Results Over a 24-month period, a total of 69 patients underwent minimally invasive lobectomy (35 robotic, 34 VATS). Patients in each group were similar in age and clinical stage. Robotic upper lobectomy operative times were longer than VATS (172 vs 134 minutes; P = .001), with no significant difference in lower lobectomies noted (140 vs 123 minutes; P = .1). Median length of stay was 3 days in both groups, and the median number of lymph nodes harvested was 18 (robotic) versus 16 (VATS; P = .42). Morbidity and mortality for robotic versus VATS were 11% versus 18% ( P = .46) and 0% versus 3% ( P = .49), respectively. Conclusions There does not seem to be a significant advantage for an established VATS lobectomy surgeon to transition to robotics based on clinical outcomes. The learning curve for robotic upper lobectomies seems to be more significant than that for lower lobectomies.

Thymic malignancies are relatively rare tumors. A general lack of knowledge, misconceptions about benignancy, confusion about the definition of terms, and variability in reporting of outcomes have further hampered progress in these diseases. The International Thymic Malignancy Interest Group has emerged to counter these challenges and has brought together a worldwide multidisciplinary community determined to improve outcomes for these patients. Although the organization is young (initiated in 2010), major early accomplishments have created a foundation and infrastructure for scientific research. These include consensus definitions of terms, an unprecedented global database, development of practical clinical resources and, together with the International Association for the Study of Lung Cancer, development of proposals for the first formal stage classification of these malignant tumors. Many articles have been published or are under way, and a second phase of projects building on the early success is proceeding. The greatest accomplishment of the International Thymic Malignancy Interest Group lies in the establishment of an open culture of collaboration and the engagement of a broad group of individuals united by a common mission. It is a testament to what can be achieved, despite ongoing and inherent challenges, by determination and a collective effort.

Objective Radiofrequency ablation can eradicate Barrett's esophagus successfully in the majority of cases. We sought to determine (1) how often intestinal metaplasia is detected during follow-up endoscopy after successful ablation and (2) patterns of persistent/recurrent intestinal metaplasia. Methods Patients ablated successfully during a phase II clinical trial of radiofrequency ablation for Barrett's esophagus were followed using endoscopic surveillance according to a defined protocol. Systematic biopsies were performed in all patients throughout the neosquamous epithelium as well as at the gastroesophageal junction, and patterns of recurrent or persistent intestinal metaplasia were documented. Results Fifty-three patients were ablated successfully during this single-institution clinical trial. A total of 151 follow-up endoscopies were performed (range, 1-5 endoscopies per patient) and 2492 biopsies were obtained, of which 604 (24%) were from the gastroesophageal junction. The median follow-up period was 18 months (range, 3-50 months). Recurrent/persistent intestinal metaplasia was detected in 14 patients (26%) in 3 distinct patterns: endoscopically invisible intestinal metaplasia underneath the neosquamous epithelium (buried glands) in 3 patients, visible recurrence in the tubular esophagus in 3 patients, and intestinal metaplasia of the gastroesophageal junction (with a squamous-lined tubular esophagus) in 10 patients. Dysplasia or cancer was not detected in any patient during the follow-up period. Conclusions Recurrent/persistent intestinal metaplasia after successful radiofrequency ablation of Barrett's esophagus is relatively common. This finding has implications for the continued surveillance of patients who are ablated successfully.

Objectives The latest World Health Organization (WHO) histological classification divides thymic epithelial tumours in thymomas and thymic carcinomas (TCs), the latter also including the neuroendocrine thymic tumours (NETTs). NETTs and other TC histotypes have been described to have a significantly lower survival than thymomas, but these two groups of tumours have rarely been compared directly. Using the European Society of Thoracic Surgeons and the International Thymic Malignancy Interest Group datasets, we wanted to study this issue. Methods This is a retrospective multicentre cohort study of patients operated for TC. Outcome measures were overall survival (OS) and recurrence-free survival (RFS). OS was analysed using the Kaplan-Meier method and RFS was assessed using competing risk analysis. The association with clinical and prognostic factors for OS and RFS was evaluated with log-rank test and Gray's test, respectively. Results A total of 1247 tumours (1042 TCs) were collected between 1984 and 2012. A R0 resection was performed in 363 TCs and in 52 NETTs. The median follow-up was 4.4 years for TCs and 4.1 years for NETTs. Owing to the missing values for survival information, a total of 728 TC patients and 132 NETTs were included in the OS analysis. Among them, 262 TC and 39 NETT patients died. The median OS was 6.6 years for TC and 7.5 years for NETTs. The overall 5-year survival rates were 60% for TC and 68% for NETTs; 10-year survival rates were 40% for TCs and 39% for NETTs (P = 0.19). Five-year RFS was 0.35 and 0.34 for TCs and NETTs (P = 0.36). On multivariate analysis, histology did not influence either OS (P = 0.79) or RFS (P = 0.59). Conclusions This represents the largest clinical series of TCs and NETTs collected. Despite the biological aggressiveness of these rare neoplasms, the 5-year survival rate after resection is over 60% and TCs and NETT showed a similar rate of survival and recurrences after surgery.

Adjuvant radiotherapy after complete resection of localized, invasive thymic epithelial tumors is considered by many to be the standard of care, despite little supporting literature. We hypothesized that individual studies may lack statistical power to demonstrate a reduction in recurrence with this approach, but meta-analysis of published data may allow for more adequate statistical evaluation. Analysis of data from 592 patients with completely resected stage II or III thymic epithelial tumors, however, revealed no statistically significant reduction in recurrence after adjuvant radiotherapy (odds ratio 1.05; 95% confidence interval: 0.63 to 1.75; p = 0.840). Additionally, the majority of publications suggest that the most common sites of recurrence are the lung, pleura, and diaphragm, even when incompletely resected patients are included.

Objective There has been an increase in interest in endoscopic therapy (ET) for intramucosal (T1a) or submucosal (T1b) esophageal carcinoma. The objective of the present study was to determine the prevalence of nodal metastases, lymphatic vascular invasion, and multifocal neoplasia in patients with pT1 esophageal carcinoma who underwent esophagectomy without preoperative therapy and assess their potential implication for ET. Methods We retrospectively reviewed the records of all patients who underwent esophagectomy without preoperative therapy for pT1 esophageal cancer. A detailed review of all pathology reports was performed to identify relevant pathologic criteria including depth of invasion (T1a or T1b), cell type (adenocarcinoma/squamous), tumor differentiation (poor vs. well/moderate), extent of Barrett esophagus (short segment [SSBE] and long segment [LSBE]), nodal status, lymphovascular invasion (LVI), and the presence of multifocal neoplasia (MFN) (high-grade dysplasia or invasive carcinoma). Overall survival and disease-specific survival were determined by the Kaplan-Meier method. Results There were 75 consecutive patients (58 men, 17 women) between January 1994 and September 2006. Median age was 68 years. Hospital mortality was 2.6% (2 of 75). Thirty patients had T1a and 45 had T1b. Sixty patients had adenocarcinoma. Nodal metastases were present in 2 of 30 (6%) T1a and 8 of 45 (17.5%) T1b tumors. MFN was present in 30% (9 of 30) of T1a tumors and 29% (13 of 45) of T1b tumors. All 9 patients with LVI had T1b tumors. Collectively, 10 of 30 (33.3%) patients with T1a and 25 of 45 (58%) with T1b had MFN, LVI, or nodal metastases. Forty-nine patients had adenocarcinoma with associated BE (23 SSBE, 26 LSBE). There was no difference between patients with SSBE and those with LSBE in the incidence of nodal disease (2 of 23 vs. 2 of 26) but a significant difference in the incidence of MFN (3 of 23 vs. 13 of 26, P = 0.006). Four patients with squamous carcinoma had nodal metastases and 5 had MFN. Overall 5-year survival was 78% (T1a:90% T1b: 71%, P = 0.07). Five-year disease-specific survival was 86.5% (T1a: 96.7%, T1b: 79.6%, P = 0.06). Conclusion The combined high incidence of MFN, LVI, and occult nodal metastases does not support the use of ET in patients with T1 esophageal cancer regardless of depth of invasion, cell type, differentiation or extent of BE. ET may be of value in patients in whom surgical risk is considered prohibitive.

In patients deemed to have clinical stage I for non-small cell lung cancer (NSCLC) after computerized tomography (CT) and positron emission tomography (PET) scans, the utility of mediastinoscopy to detect occult mediastinal metastases is unclear. The goal of this study was to analyze the risk factors for occult mediastinal metastases in this subset of patients.We conducted a retrospective review during a 7-year period to identify patients with potentially operable clinical stage I NSCLC screened by CT and PET scans. Medical records were reviewed, and the prevalence of pathologic N2 disease was analyzed according to clinical tumor location, size, histology, and PET uptake of the primary tumor.Of 224 patients identified with clinical stage I NSCLC with a CT-negative and PET-negative mediastinum, 16 patients had pathologic N2 disease proven by mediastinoscopy (n = 11) or after resection (n = 5). The overall prevalence of histologically confirmed N2 disease was 6.5% in clinical T1 patients and 8.7% in clinical T2 patients. Central tumors had a higher prevalence of N2 disease compared with peripheral tumors, 21.6% versus 2.9% (p0.001). Larger clinical T size predicted a higher prevalence of occult N2 disease (p0.001). All 16 patients with occult N2 metastases had adenocarcinoma as the primary tumor cell type. When the PET maximum standardized uptake value (SUV(max)) of the primary tumors was analyzed, patients with occult N2 metastases had a higher median SUV(max) of the primary tumor compared with patients without N2 metastases, 6.0 g/mL versus 3.6 g/mL (p = 0.017).For patients deemed at clinical stage I NSCLC by CT and PET, the prevalence of missed N2 metastases increased significantly with larger tumor size and central location. Adenocarcinoma cell type and a high PET SUV(max) of the primary tumor were other risk factors. Mediastinoscopy may have improved yield in the select subset of patients with one or more risk factor.

Background To determine the eventual outcome of abnormalities detected on surveillance computed tomography (CT) in patients with previously resected nonsmall-cell lung cancer (NSCLC), and to assess the accuracy of CT when used by the thoracic surgeon, and to determine the characteristics of abnormalities on CT that correlate with the development of recurrent NSCLC. Methods A cohort of patients who had abnormal postoperative CT scans of the chest and upper abdomen in 2002 were followed up into 2005. Abnormalities consisted of pulmonary nodules, pleural effusions, or adenopathy. Data collected included recurrence patterns, the availability of previous scans for comparison, the interval between initial resection and the abnormal CT, nodule size, growth, and multiplicity, as well as progression of pleural effusions or adenopathy. Results In all, 105 scans in 92 patients were read as abnormal in 2002 by the radiologist. After further investigation or follow-up, or both, for a mean of 3.2 years, 78% of patients who had recurrent NSCLC had their site of first recurrence inside the chest. The negative predictive value of CT when used by the thoracic surgeon was 99%; however, the positive predictive value was only 53%. Abnormalities that correlated with the diagnosis of recurrent cancer included pulmonary nodules that either grew or were larger than 1 cm and pleural effusions that developed after the first postoperative year. Conclusions Intrathoracic recurrent NSCLC was rarely missed by the surgeon utilizing surveillance CT, but a significant number of negative investigations were generated by its use. Characteristics of abnormal surveillance CT findings exist that correlate with the presence of malignancy.

Background Postoperative surveillance with chest computed tomography (CT) is often performed in patients who have undergone resection of non-small cell lung cancer (NSCLC), despite lack of supporting data. This study involves the creation of a decision analysis model to predict the cost effectiveness of postoperative surveillance CT. Methods A decision analysis model was created in which a hypothetical cohort of patients underwent annual chest CT after resection of a stage IA NSCLC. The incidence of second primary lung cancer (SPLC), sensitivity and specificity of CT, as well as survival after resection of initial primary and SPLC were derived from published literature. The cost of CT and other procedures prompted by a positive finding on CT was calculated from Medicare reimbursement schedules. Cost effectiveness was defined as a cost of less than $60,000 per quality-adjusted life-year gained in the cohort under surveillance compared with controls under no surveillance. Results In the initial (base case) analysis, the cost of surveillance CT was $47,676 per quality-adjusted life-year gained, implying cost effectiveness. However, factors that rendered surveillance CT cost ineffective were (1) age at entry into the surveillance program greater than 65 years, (2) cost of CT greater than $700, (3) incidence of SPLC of less than 1.6% per patient per year of follow-up, and (4) a false positive rate of surveillance CT greater than 14%. Conclusions Surveillance with postoperative CT may be a cost-effective intervention to detect SPLC in selected patients with previously resected stage IA NSCLC.

Despite renewed interest in early detection of lung cancer, the relationship between tumor size and survival remains controversial. The objective of this study was to evaluate the relationship between size and stage in patients with T1 (or = 3.0 cm) non-small cell lung cancer (NSCLC).A retrospective review of a lung cancer database from 1995 to 2003 identified 503 patients with completely resected invasive NSCLC with tumorsor = 3 cm. All clinical and pathologic characteristics were recorded. Univariate associations between nodal status and other prognostic factors were explored by chi2 and t tests. The independent effect of tumor size2 cm vsor = 2 cm on the risk of nodal disease was analyzed using a logistic regression model.Of the 503 patients, 324 patients (64.4%) had stage IA disease, 52 patients (10.3%) had stage IB disease, 37 patients (7.4%) had stage IIA disease, 15 patients (3%) had stage IIB disease, 43 patients (8.6%) had stage IIIA disease, 24 patients (4.8%) had stage IIIB disease, and 8 patients (1.6%) had stage IV disease. One hundred patients (19.9%) had nodal metastases. The mean (+/- SD) tumor size of cases without nodal disease was 1.90 +/- 0.67 cm, compared to 2.18 +/- 0.69 cm for node-positive tumors (p = 0.0003; 95% confidence interval [CI] for mean difference, 0.13 to 0.43). Forty-eight of 308 patients (15.6%) with smaller carcinomas (or = 2.0 cm) compared to 52 of 195 patients (26.7%) with carcinomas2.0 cm had nodal metastases (p = 0.002). Exploratory multivariate analysis revealed that only tumor size (or = 2.0 cm [referent] vs2.0 cm) affected nodal status and thus stage (adjusted odds ratio, 2.0; 95% CI, 1.3 to 3.1; p = 0.002).Primary invasive NSCLC2.0 cm was twice as likely to have nodal metastases than carcinomasor = 2.0 cm. Our results suggest that in lung cancer smaller lesions may represent earlier stage disease. These results also suggest the need for further subclassification by tumor size within the current International Union Against Cancer/American Joint Committee on Cancer stage I, with tumors2 cm in size contained in a separate substage. This refinement may help to better clarify which patients might benefit from novel adjuvant or neoadjuvant therapeutic interventions.

Background Induction therapy is a common treatment modality for patients with stage IIIA non-small cell lung cancer (NSCLC). Although mediastinal nodal downstaging after induction therapy is generally considered a favorable prognostic feature, the benefit of resection in the presence of residual N 2 disease is controversial. In this study we analyzed our experience with resection after induction chemotherapy in patients with residual N 2 disease to more precisely define the role of surgical resection in this group of patients. Methods In this retrospective analysis, we reviewed the records of 78 patients with N 2 disease who received induction therapy with preoperative intent between 1990 and 2003. All patients had potentially resectable disease. Survival analysis was performed using the Kaplan-Meier method. A Cox proportional hazards regression model was used to evaluate multiple prognostic factors. Results There were 78 patients (39 men) with a median age of 64 years. Sixty had nonsquamous histology. Resection was performed in 52 patients (47 R 0 ). Hospital mortality was 1.9%. A complete pathologic response occurred in 2 of 52 (3.8%) patients and 19 of 52 (36%) patients had no residual N 2 disease. Overall 5-year survival for resected patients was 23%. Overall 5-year survival was 30% for N 0 -N 1 patients and 19% for those with residual N 2 disease. Multivariable analysis identified clinical response to therapy ( p = 0.0007) and histology ( p = 0.01), but not residual N 2 disease ( p = 0.65), as important prognostic variables. Conclusions Surgical resection may be a viable option for patients with residual N 2 disease after induction chemotherapy, provided an R 0 resection can be performed.

Objective We sought to determine the prevalence of defined abnormalities on surveillance computed tomography after complete resection for non–small cell lung cancer, as well as the nature and cost of further testing prompted by these abnormalities. We also sought to determine whether resectable metachronous lung cancer can be detected with surveillance scans. Methods A retrospective analysis was performed of all patients who presented for follow-up in 2002 after complete resection for non–small cell lung cancer. Data collected included demographics, clinicopathologic features of the initial lung cancer, the number and results of surveillance computed tomographic scans performed in 2002, the attending surgeons' impressions of the surveillance scans, the nature of any abnormalities and further diagnostic testing prompted by these abnormalities, and the nature of any lung cancer detected on surveillance scans, as well as the treatment rendered. The cost of surveillance scanning and associated diagnostics was computed by using Medicare fee schedules. Results Two hundred thirteen patients met the criteria for inclusion in the study cohort. One hundred sixty-eight surveillance scans were performed in 140 of these patients. One hundred five scans were interpreted as abnormal by the radiologist with regard to pulmonary nodules, adenopathy, or pleural fluid, but the surgeon was suspicious for recurrent or new primary lung cancer in only 32 of 105 scans. Further workup revealed recurrent or new primary lung cancer in 16 of 32 patients, with 6 undergoing resection for localized disease. The cost of the surveillance scans and associated care in the study cohort were 16.6% higher than the cost of care in a hypothetically identical cohort not subjected to surveillance scanning. Conclusions Surveillance computed tomography is frequently abnormal after complete resection for non–small cell lung cancer; however, the majority of these abnormalities are not clinically suspicious. Resectable metachronous lung cancer is detected by using surveillance scanning; however, the use of this modality can be associated with increased cost.

Background Angiogenesis is a multistep process in which the endothelial cell plays a pivotal role. We hypothesized that the combination of two antiangiogenic agents with distinct mechanisms of action would more effectively inhibit tumor growth than either agent alone in a murine mesothelioma model. Methods A syngeneic murine mesothelioma flank tumor model (AB-12) was established in BALB/c mice. Separate adenovirus vectors expressing the cDNAs for human pigment epithelium-derived factor (AdPEDF) and a soluble form of the human vascular endothelial growth factor receptor-1 (Adsflt-1) were administered intratumorally. End points measured included tumor size, animal survival, and microvessel density using CD31 immunohistochemistry. An orthotopic model of mesothelioma was established by implanting AB-12 cells into the murine pleural cavity. Simultaneously, AdPEDF and Adsflt-1 were instilled intrapleurally and tumor burden and survival were recorded. The development of pulmonary emphysema was also assessed by calculating the mean linear intercept (a measure of interalveolar septal distance) in histologic lung sections from tumor-free mice after vector administration. Results In the flank tumor model, the combination of AdPEDF and Adsflt-1 inhibited tumor growth, prolonged survival, and decreased microvessel density more profoundly compared with either AdPEDF or Adsflt-1 alone. In the orthotopic model, the combination was also more effective in prolonging survival. Intrapleural AdPEDF or Adsflt-1 did not increase the mean linear intercept compared with controls in tumor-free mice. Conclusions In this murine model, inhibiting multiple mechanisms of angiogenesis using two agents is a more effective antineoplastic strategy than using either agent alone. In addition, instillation of antiangiogenic gene transfer vectors into the pleural space does not result in histologic evidence of pulmonary emphysema.

Objective Tumors down-regulate major histocompatibility complex class I expression, escaping recognition by the cellular immune response. We hypothesized that augmentation of tumor cell class I expression by interferon-gamma would enhance the cellular antitumor immune response and cure rate of an active immunotherapy strategy. Methods B16.F10 tumor cells were exposed to interferon-gamma in culture, and class I expression was quantified using flow cytometry. Syngeneic mice bearing established tumors were injected with interferon-gamma (5000 U, intraperitoneal), and class I expression was assessed using immunohistochemistry. Tumor-specific cytotoxic T lymphocytes were induced in mice by an intratumoral injection of AdCD40L (5 × 10 10 particles), an adenovirus gene transfer vector-based immunotherapy strategy previously demonstrated to augment cellular antitumor immunity. A conjugate-formation assay and the enzyme-linked immunospot assay were used to evaluate the binding and activation of cytotoxic T lymphocytes, respectively. Interferon-gamma was administered to tumor-bearing mice concomitantly with intratumoral AdCD40L. End points measured included the frequencies of cytotoxic T lymphocytes using the enzyme-linked immunospot assay, tumor size, and mouse survival. The role of class I expression was further evaluated by monoclonal antibody blockade in both in vitro and in vivo experiments. Results B16.F10 cells exposed to interferon-gamma expressed significantly more class I, both in vitro and in vivo, and were able to bind to and activate cytotoxic T lymphocytes more efficiently than untreated cells. Cytotoxic T-lymphocyte frequencies, tumor regression, and the cure rate induced by AdCD40L were augmented by the addition of a single dose of interferon-gamma in tumor-bearing mice. These in vitro and in vivo effects of interferon-gamma were attenuated by class I monoclonal antibody blockade. Conclusions Up-regulation of class I expression using interferon-gamma enhances the cellular antitumor immune response and cure rate of AdCD40L, an active immunotherapy strategy. This approach may be useful for human tumors that lack class I expression.

Objective Paclitaxel has one of the highest response rates when used as a single agent in patients with esophageal cancer. The combination of paclitaxel and carboplatin has been shown to be a well-tolerated and safe regimen in non–small cell lung cancer. The objective of this study was to determine the efficacy of preoperative paclitaxel and carboplatin in patients with carcinoma of the esophagus. Patients and methods A phase II trial was initiated in January 1999 and concluded in January 2001. All patients had potentially resectable disease (including clinical T4 lesions). Patients with stage I disease and those with visceral metastases were excluded. All underwent preoperative computed tomography scanning and endosonography for staging. Paclitaxel (200 mg/m 2 ) and carboplatin (area under the curve=6) were given on days 1 and 22. Esophagectomy was carried out on weeks 6 to 8. Results Twenty-six (11 epidermoid, 15 adenocarcinoma) patients completed the trial. Median age was 61.5 and 85% were men. Preoperative staging showed: stage IIA, 6 patients; stage IIB, 1 patient; and stage III, 19 patients. All patients completed their preoperative chemotherapy. There was no unexpected chemotherapy-related toxicity. A major clinical response was achieved in 16 patients (61%: 19% complete, 42% partial). Resectability was 77% (20/26). A complete pathologic response was seen in 11% of all patients and in 25% of those with epidermoid cancer. Hospital mortality and morbidity were 4 and 27%, respectively. Overall 3-year survival was 48% (64% for resected patients, median not reached). All 6 unresectable patients died within 6 months of exploration. Conclusion Paclitaxel-carboplatin combination is a safe and well-tolerated regimen for esophageal cancer with clinical response rates comparable to historical controls. This regimen may be especially suitable for patients with epidermoid cancer, who had a 25% pathological complete response in this report.

Purpose: Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non–small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2(PGE2).Methods: In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib.Results: All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2detected in primary tumors after treatment with paclitaxel and carboplatin alone.Conclusion: In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

Macrophage-derived chemokine is chemotactic for a variety of leukocytes, and has been shown to be involved in T H 2-mediated cellular immunity. To evaluate the role of this chemokine in tumor immunity in vivo, an adenovirus vector encoding the human macrophage-derived chemokine cDNA (AdMDC) was administered to established murine tumors. Gene transfer with AdMDC significantly inhibited tumor growth and prolonged animal survival. AdMDC was not directly cytotoxic to tumor cells, but splenocytes from animals that received intratumoral AdMDC were able to lyse syngeneic tumor cells, and purified splenic CD8 + cells secreted interferon-γ in a tumor-specific manner. The antitumor activity of AdMDC was lost in mice lacking CD8 + T lymphocytes, but surprisingly, it was preserved in animals lacking CD4 + cells, as was the systemic cytotoxic T lymphocyte response. Systemic NK cells did not play a role in the antitumor immune response induced by AdMDC. Experiments using knockout mice demonstrated that host expression of MHC Class I, but not Class II, IL-4, or IL-12, was necessary for AdMDC to exert its antitumor effect, and immunohistochemistry demonstrated infiltrates of CD8 + and CD86 + cells, but not CD4 + cells in treated tumors. These studies highlight a new function for macrophage-derived chemokine by demonstrating that it possesses in vivo antitumor activity with CD8 + T cells as the effector cells, and interestingly, that the CD4 + cell/MHC II pathway of CD8 + cell activation is not required for the antitumor effects of this chemokine.

Because advanced age is the strongest independent risk factor for the development of supraventricular arrhythmias after lung resection, we compared the incidence and premorbid events of supraventricular arrhythmias after pneumonectomy in young and elderly dogs with the aim of better understanding potential age-related arrhythmogenic mechanisms. Right pneumonectomy was performed in 15 male mongrel dogs ("old"or =8 yr [n = 8], "young"4 yr [n = 7]) and the electrocardiogram continuously recorded by an implantable telemetry system for 1 wk before euthanizing. After surgery, 7 of 8 older animals (88%) developed a total of 23 episodes of sustained (30 s) paroxysmal supraventricular tachycardia (SVT), compared with 0 of 7 (0%) young dogs, P = 0.0014. Analysis of heart rate over the 60 min preceding the onset of SVT revealed a progressive increase in sinus rhythm beginning 15 min before the arrhythmia. Comparison of the heart rate and rhythm obtained in younger animals from the corresponding postoperative hour demonstrated that although older animals developed more atrial (P = 0.03) and ventricular premature contractions (P = 0.056) and episodes of nonsustained ventricular tachycardia (P = 0.01), heart rate was similar for both groups until the increase in elderly dogs preceding the onset of SVT. Histologic examination of the atria showed interstitial fibrosis in old but not young animals. In addition, 4 of 8 (50%) elderly animals exhibited an inflammatory response within the atria consistent with acute myo- and epicarditis. We conclude that elderly dogs have an increased supraventricular arrhythmogenic potential within the first week after pneumonectomy than younger animals, perhaps because of increased atrial fibrosis and inflammation. Heart rate analysis before SVT onset suggests that adrenergic predominance was a probable responsible trigger.In this canine pneumonectomy model, advanced age was associated with an increased incidence of supraventricular arrhythmias, perhaps because of increased atrial fibrosis and inflammation.

PURPOSE: Assessment of long-term results of combined-modality therapy for resectable non–small-cell lung cancer is hampered by insufficient follow-up and small patient numbers. To evaluate this, we reviewed our collective experience. PATIENTS AND METHODS: This study was a retrospective chart review recording demographics, tumor stage, treatment, and outcome of consecutive patients undergoing surgery. Survival was analyzed by Kaplan-Meier, and prognostic factors were analyzed by log-rank and Cox regression. RESULTS: From January 1993 to December 1999, 470 patients were treated, with follow-up in 446: 27 stage I, 55 stage II, 316 stage III, 43 stage IV (solitary M1), and five uncertain. Chemotherapy was mitomycin/vinblastine/cisplatin (174 patients [39.0%]), carboplatin/paclitaxel (148 [33.2%]), and other combination (124 [27.8%]); 75 patients (16.8%) received induction radiation. Resection was complete in 77.4%, incomplete in 8.3%, attempted but with gross residual disease afterward in 1.8%, and not performed in 12.6%. Pathologic complete response occurred in 20 patients (4.5%). With median follow-up of 31.0 months for patients still alive, median and 3-year survival for pathologic stages 0, I, II, III, and IV were more than 90 months, 73%; 42 months, 52%; 23 months, 35%; 16 months, 28%; and 16 months, 23% (P < .001). In a multivariate analysis, age, complete resection, pathologic stage, and pneumonectomy, but not induction regimen, significantly influenced survival. CONCLUSION: Although pathologic complete response outside the protocol setting is low, survival of this large patient cohort is comparable to that of patients in published combined-modality trials. Survival is significantly influenced by patient age, complete resection, pathologic stage, and pneumonectomy. These results can help guide standard clinical practice and emphasize the need for novel induction regimens.

To address the effect of adenovirus (Ad) gene transfer vector transduction on the diverse functions of dendritic cells, we used an Ad vector encoding no transgene (AdNull) to transduce mouse bone-marrow-derived dendritic cells (BMDC). Initial experiments using an Ad vector encoding a marker gene (AdGFP, jellyfish green fluorescent protein) showed that the optimal ratio of infectious Ad particles to each cell was 100, when both transgene expression and resultant BMDC viability were taken into account. Exposure to AdNull resulted in upregulation of both surface activation markers (CD40, MHC class II, B7.1, B7.2, ICAM-1) and IL-12 expression by BMDC. AdNull activation of BMDC was observed in multiple strains of mice. Despite this, AdNull-transduced BMDC displayed only modestly impaired antigen uptake ability, as demonstrated in macropinocytosis and phagocytosis assays, in vitro. However, Ad-modified BMDC migrated to regional lymph nodes five times more efficiently than sham-transduced BMDC in vivo. In addition, Ad transduction significantly enhanced the ability of BMDC to present a model peptide antigen to T-lymphocyte hybridoma cells at low BMDC:T cell ratios. We conclude that Ad modification, in and of itself, induces a state of activation in mouse BMDC. This activation, albeit mild compared with that induced by other stimuli, produces measurable effects of the specific immunological functions of these antigen-presenting cells.

We hypothesized that adenovirus-mediated transfer of the vascular endothelial growth factor (VEGF121) complementary DNA (cDNA) to murine laparotomy fascial wounds would enhance vascularity and bursting strength.Microfibrillar collagen sponges saturated with adenovirus (Ad) vectors encoding for the human VEGF121 cDNA (Ad(CU)VEGF121.1), a control marker gene (Ad beta gal, AdLuc) or no transgene (AdNull) were sutured to fascial edges during laparotomy closure in normal mice and mice treated with dexamethasone. Endpoints addressed included transgene expression in the fascia and surrounding tissue, the number of blood vessels in the healing wound determined using immunostaining, and wound bursting strength using a calibrated tensinometer.Transgene expression was detected readily in the fascial edges, but only marginally detectable in neighboring tissues. In normal mice and mice treated with dexamethasone, no differences were observed at 7 days. Strikingly, however, 21 days after wound closure/therapy, significantly more blood vessels were present in the wounds that received the VEGF121 vector compared with controls (normal: AdNull: 4.2 +/- 1.8; Ad(CU)VEGF121.1: 11.2 +/- 1.2; P.05; dexamethasone: AdNull: 1.4 +/- 0.8; Ad(CU)VEGF121.1: 5.4 +/- 1.2; P.05), and bursting strength was significantly higher in VEGF121-treated wounds (normal: AdNull: 665 +/- 68 mN/mm; Ad(CU)VEGF121.1: 956 +/- 82 mN/mm; P.0005; dexamethasone: AdNull: 234 +/- 111 mN/mm; Ad(CU)VEGF121.1: 592 +/- 121 mN/mm; P.03).Adenovirus-mediated gene transfer to healing fascial wounds is achieved readily using a microfibrillar collagen sponge, with transfer of the human VEGF121 cDNA significantly enhancing wound vascularity and bursting strength in normal mice, as well as in mice treated with dexamethasone.

Background . The 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) imaging is an advance over computed tomography alone in the staging of untreated nonsmall cell lung cancer (NSCLC). Aside from one 9-patient study, there are no data comparing FDG-PET imaging with surgical staging of NSCLC after induction therapy. Methods . We reviewed our institutional experience with FDG-PET imaging followed by surgical staging of nonsmall cell lung cancer after induction therapy. A nuclear physician blinded to surgical findings reviewed the FDG-PET scans and assigned a clinical TNM stage. A thoracic surgeon assigned a pathologic TNM stage. Then the clinical TNM stage and the pathologic TNM stage were compared. Results . Fifty-six patients (30 males and 26 females; median, age 60) with nonsmall cell lung cancer underwent chemotherapy (40 patients), chemoradiation (11 patients), or radiation alone (5 patients) followed by PET and operations. PET had a positive predictive value of 98% for detecting residual viable disease in the primary tumor. PET over-staged nodal status in 33% of patients, under staged nodal status in 15%, and was correct in 52%. PET correctly classified all patients with M1 disease. Conclusions . Positron emission tomography after induction therapy accurately detects residual viable primary tumor, but not the involvement of mediastinal lymph nodes.

Although tumor necrosis factor alpha (TNF-alpha) is a potent cytokine with a myriad of innate immune antitumor properties, systemic administration of TNF-alpha is associated with significant toxicity, limiting the use of the TNF-alpha protein as an antitumor therapeutic. On the basis of the knowledge that dendritic cells (DCs) play a central role in initiating antitumor adaptive immune responses, we hypothesized that intratumoral administration of low doses of an adenovirus encoding TNF-alpha (AdTNF-alpha) together with syngeneic DCs would act synergistically to suppress preexisting tumors. As a model, four different tumor cell lines, all resistant in vitro to the TNF-alpha protein, were implanted in syngeneic mice, and established tumors received intratumor AdTNF-alpha alone or in combination with DCs. At high doses (10(9) PFU), AdTNF-alpha alone suppressed tumor growth, but was associated with systemic toxicity. A 100-fold lower AdTNF-alpha concentration (10(7) PFU) or high doses of the control vector AdNull had no systemic toxicity, but also minimal suppression of tumor growth. In contrast, local administration of the low dose (10(7) PFU) of AdTNF-alpha in combination with syngeneic DCs (AdTNF-alpha + DCs) elicited marked tumor suppression without toxicity. Administration of AdTNF-alpha + DCs into tumors elicited tumor-specific cytotoxic T cells and protected animals against subsequent challenge with the same tumor, suggesting that AdTNF-alpha + DC therapy induced tumor-specific adaptive immune host responses. Consistent with this concept, studies with syngeneic knockout mice showed that MHC class I molecules on DCs as well as CD8(+) T cells were necessary for the antitumor effect of intratumor AdTNF-alpha + DCs. These data demonstrate that the combination of intratumoral administration of the TNF-alpha cDNA together with naive DCs can evoke tumor suppression without systemic toxicity, providing a new paradigm for the use of TNF-alpha as antitumor therapy.

Background . The risks of complications in patients undergoing thoracotomy after neoadjuvant therapy for nonsmall cell lung cancer remain controversial. We reviewed our experience to define it further. Methods . All patients undergoing thoracotomy after induction chemotherapy from 1993 through 1999 were reviewed. Univariate and multivariate methods for logistic regression model were used to identify predictors of adverse events. Results . Induction chemotherapy included mitomycin, vinblastine, and cisplatin (179 patients), carboplatin and paclitaxel (152 patients), and other combinations (139 patients). Eighty-five patients (18%) received preoperative radiation. Operations were pneumonectomy (97 patients), lobectomy (297 patients), lesser resection (18 patients), and exploration only (58 patients). Total mortality was 7 of 297 (2.4%) and 11 of 97 (11.3%) for all lobectomies and pneumonectomies, respectively, but mortality was 11 of 46 (23.9%) for right pneumonectomy. Complications developed in 179 patients (38%). By multiple regression analysis, right pneumonectomy ( p = 0.02), blood loss ( p = 0.01), and forced expiratory volume in one second (percent predicted) ( p = 0.01) predicted complications. No factor emerged to explain this high right pneumonectomy mortality rate. Conclusions . Pulmonary resection after neoadjuvant therapy is associated with acceptable overall morbidity and mortality. However, right pneumonectomy is associated with a significantly increased risk and should be performed only in selected patients.

Regional lymph nodes (RLNs) possess important immune functions and represent a major pathway of metastasis for solid tumors. Given these facts, the ability to transfer exogenous genes to the RLNs with the goal of manipulating the local immunological milieu would be desirable. On the basis of the hypothesis that a significant proportion of adenovirus (Ad) gene transfer vectors traffic through the lymphatics, E1-E3- Ad vectors were injected into the hind footpad of C3H/He mice and the RLNs assessed for vector trafficking and transgene expression. A low dose (10(9) particles) of an Ad vector encoding the firefly luciferase gene (Ad-CMV.Luc) resulted in luciferase expression only in the injection site and RLNs, with no detectable systemic (liver, spleen, lung) expression. At a higher dose (10(11) particles), some expression could be detected systemically in addition to the RLNs, but at levels in liver 14-fold less than in the RLNs. Transgene expression in the RLNs was transient, peaking at 1 day, decreasing markedly by 7 days. At high doses (10(11) particles), interruption of draining lymphatics decreased the amount of systemic dissemination 22-fold, suggesting that a large proportion of the vector trafficks through the lymphatics before reaching the systemic circulation. Administration of a vector encoding the jellyfish green fluorescent protein gene (AdCMV.GFP, 10(11) particles) showed that transgene expression in the RLNs was primarily in the cortical area. After footpad injection of a fluorescent-labeled Ad vector (Cy3-AdCMV.Null), fluorescent virions were visualized in the draining lymph. Regional lymph collected from animals injected in the footpad with AdCMV.Luc (10(11) particles) contained functional vector. Augmentation of local immune function in the RLNs was achieved by footpad administration of an Ad vector encoding murine IL-12, resulting in high mIL-12 and IFN-gamma levels in the regional, but not distant, nodes. These data demonstrate that expression of exogenous genes in RLNs is easily accomplished with Ad vectors, Ad vector dissemination occurs primarily via the lymphatics after footpad administration in mice, and basic immune functions in the RLNs can be manipulated by Ad-mediated gene transfer in vivo.

Minimally invasive pulmonary resection (MIPR) for lung cancer has become standard in many centers, and is slowly being adopted throughout the United States. An abundance of literature supports MIPR over traditional thoracotomy in terms of short-term surgical outcomes with no oncologic inferiority, and perhaps benefit. 1 What has become the latest point of contention, however, is not whether or not MIPR should be performed, but what instrumentation should be used to perform it. In this regard, Agzarian et al 2 have performed a systematic review of published literature (no randomized, controlled trials [RCT]) concerning robotic-assisted thoracic surgery (RATS), ultimately comparing it to nonrobotic MIPR (video assisted thoracic surgery (VATS)) as well as traditional thoracotomy. As one would anticipate, RATS appeared to provide superior outcomes compared to traditional thoracotomy. However, no significant differences were appreciated in surgical and oncologic outcomes between RATS and VATS, with the exception that RATS appeared to be more costlier than VATS. The authors concluded (as have other investigators that have evaluated this question) that a prospective randomized trial is needed to investigate differences in outcomes between RATS and VATS. Is this a question that the thoracic surgical community really needs to attempt to answer in a RCT? We would argue “no,” for several reasons. First, any such trial cannot be performed in a blindedfashion.Different surgeons will need to performRATS vs VATS, which will introduce significant surgeon bias. Surgeons have different technical abilities and philosophies regarding how to conduct the operation. Some surgeons have adopted RATS because they are not comfortable in their ability to perform VATS. As a result, even if a significant difference in an outcome variable was detected in a RCT, it may be contested on this basis. Second, what is the hypothesis that would be tested in a RCT? There is no evidence to date that one approach is better than the other (with the possible exception

Primary B cell lymphoma of the central airways is a rare tumor. This report describes a case of primary B cell lymphoma of the subglottic airway in a patient with Sjogren's syndrome, which resembled a benign, cicatricial subglottic stenosis. Successful management was achieved using surgical resection with laryngotracheal reconstruction.

Generalized lymphangiomatosis management can be challenging. Surgical treatment is indicated for complications (such as chylopericardium and chylothorax) or for biopsy. An important issue for management of chylous effusions is that there is not one specific source of chyle that can be stopped through the thoracic duct ligation; instead, there is a wide abnormal network of lymphatic channels. However, the best results have been reported with pleurectomy, with or without thoracic duct ligation, whereas thoracic duct ligation alone was unsuccessful in all cases. Fibrin glue application may help control lymphatic leakage from exposed surfaces after pleurectomy. 2 Other treatment options include inter feron alfa and systemic chemotherapy with limited success, and radiation in fractioned dose has been promising for patients with extensive mediastinal disease. 5

Study objective To define the most severe form of postlobectomy atelectasis and determine its incidence, predisposing factors, and clinical ramifications. Design Retrospective case control. Setting The thoracic surgery unit at a 900-bed tertiary care hospital. Patients or participants Two hundred eighteen patients undergoing pulmonary lobectomy or bilobectomy over a 7-year time period. Measurements and results Severe postlobectomy atelectasis (SPLA) was defined as complete ipsilateral lobar or bilobar collapse with whiteout of the involved lobe(s) and mediastinal shift on the chest radiograph. Data were collected consisting of patient age, lobe(s) resected, type of postoperative pain control, length of hospital and ICU stay, preoperative pulmonary function, and single- vs double-lumen tube intubation during surgery. The incidence of SPLA was 7.8%, comprising 24.6% of all postoperative complications seen. There was no statistically significant difference in patient age, preoperative room air Po 2 , and preoperative FEX 1 /FVC ratio for the SPLA group vs the group without this complication. Patients with SPLA had significantly longer ICU stays (112.7 h vs 28.4 h; p Conclusions We conclude that SPLA as defined in this study is an important postoperative complication with a significant incidence. Although patients undergoing right upper lobectomy are markedly predisposed to this problem, the exact pathophysiology remains unclear. Factors shown to be causes of less severe forms of postoperative atelectasis do not seem to contribute to the formation of SPLA, indicating that these two complications may be two unrelated entities.

Follicular dendritic cell sarcoma is a rare malignant neoplasm of immune accessory follicular dendritic cells and may be associated with Castleman's disease which is a known precursor to follicular dendritic cell sarcomas. We report a case of a follicular dendritic cell sarcoma arising in Castleman's disease in a 63-year-old man who presented with a large posterior mediastinal mass, which required a radical pneumonectomy for complete resection.

These guidelines are an update of the evidence-based recommendations for follow-up and surveillance of patients after curative-intent therapy for lung cancer. Particular updates pertain to whether imaging studies, health-related quality-of-life (HRQOL) measures, tumor markers, and bronchoscopy improve outcomes after curative-intent therapy.Meta-analysis of Observational Studies in Epidemiology guidelines were followed for this systematic review, including published studies on posttreatment outcomes in patients who received curative-intent therapy since the previous American College of Chest Physicians subject review. Four population, intervention, comparison, and outcome questions were formulated to guide the review. The MEDLINE and CINAHL databases were searched from June 1, 2005, to July 8, 2011, to ensure overlap with the search strategies used previously.A total of 3,412 citations from MEDLINE and 431 from CINAHL were identified. Only 303 were relevant. Seventy-six of the 303 articles were deemed eligible on the basis of predefined inclusion criteria after full-text review, but only 34 provided data pertaining directly to the subject of the questions formulated to guide this review. In patients undergoing curative-intent surgical resection of non-small cell lung cancer, chest CT imaging performed at designated time intervals after resection is suggested for detecting recurrence. It is recommended that treating physicians who are able to incorporate the patient's clinical findings into decision-making processes be included in follow-up and surveillance strategies. The use of validated HRQOL instruments at baseline and during follow-up is recommended. Biomarker testing during surveillance outside clinical trials is not suggested. Surveillance bronchoscopy is suggested for patients with early central airway squamous cell carcinoma treated by curative-intent photodynamic therapy and for patients with intraluminal bronchial carcinoid tumor who have undergone curative-intent bronchoscopic treatment with Nd:YAG laser or electrocautery.There is a paucity of well-designed prospective studies specifically targeting follow-up and surveillance modalities aimed at improving survival or QOL after curative-intent therapy. Additional research is warranted to clarify which curative-intent treatment modalities affect HRQOL the most and to identify patients who are at the most risk for recurrence or impaired QOL after treatment. Further evidence is needed to determine how the frequency and duration of surveillance programs that include imaging studies, QOL measurements, tumor markers, or bronchoscopy affect patient morbidity, survival, HRQOL, and health-care costs.

Indeterminate pulmonary nodules in asymptomatic individuals are common, and their incidence is expected to increase. Although evidence-based guidelines exist for the management of these lesions, they are not in complete agreement and are often not followed, resulting in inconsistent management. A dedicated program or clinic for the management of lung nodules would allow an institution to deliver evidence-based, standardized care for patients with indeterminate nodules, and should include multidisciplinary care, state-of-the-art technology and expertise, and a patient navigation system to provide a user-friendly service for both patients and referring physicians. A dedicated pulmonary nodule clinic has many potential advantages.

The purpose of this study is to evaluate cytokine expression by peripheral blood mononuclear cells (PBMC) from stage I lung cancer patients and to confirm these expression patterns by exposing PBMCs to lung cancer cells in vitro. Five altered cytokines in stage I lung cancer patients (CCL3, IL8, IL1β, CXCL10, sIL2Rα) were identified in plasma from subjects (n = 15) before and after resection using a 30-plex panel protein assay. Gene expression studies using quantitative RT-qPCR were performed on PBMCs from stage I lung cancer patients (n = 62) before and after resection, and compared to non-cancer patients (n = 32) before and after surgery for benign disease. Co-culture experiments that exposed healthy donor PBMCs to lung cancer cells in vitro were performed to evaluate the effect on PBMC cytokine expression. PBMC gene expression of CCL3, IL8 and IL1β was higher in lung cancer patients compared to the same patients at each of four sequential timepoints after removal of their tumors, while CXCL10 and IL2Rα were essentially unchanged. This pattern was also detected when lung cancer patients were compared to non-cancer patients. When non-cancer patients underwent surgery for benign diseases, these cytokine expression changes were not demonstrable. Lung cancer cell lines, but not benign bronchial epithelial cells, induced similar changes in cytokine gene and protein expression by healthy donor PBMCs in an in vitro co-culture system. We conclude that PBMCs from stage I lung cancer patients possess distinct cytokine expression patterns compared to both non-cancer patients, and lung cancer patients following tumor removal. These expression patterns are replicated by healthy donor PBMCs exposed to lung cancer cell lines, but not benign bronchial epithelial cells in vitro. These findings have implications for understanding the immune response to lung cancer.