Scott J. Swanson

Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma : results in 183 patients

OBJECTIVES Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma. METHODS From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy. RESULTS Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05). CONCLUSIONS (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.

Surgery for Early-Stage Non-Small Cell Lung Cancer: A Systematic Review of the Video-Assisted Thoracoscopic Surgery Versus Thoracotomy Approaches to Lobectomy

Video-assisted thoracoscopic surgery (VATS) for lobectomy has been touted to provide superior outcomes, compared with thoracotomy, for patients with early-stage non-small-cell lung cancer (NSCLC). However, supporting data are limited to case series and small observational studies. We hypothesized that a systematic review of the literature would enable a more objective evaluation of the evidence in order to determine the potential superiority of the VATS approach, compared with thoracotomy, in terms of short-term morbidity and long-term survival. To identify relevant articles for inclusion in our analysis, we performed a systematic review of the MEDLINE database. We looked for randomized controlled trials, observational studies, and case series that reported outcomes after VATS or thoracotomy lobectomy for NSCLC. For statistical testing, we used a two-sided approach (alpha = 0.05) under the hypothesis that VATS lobectomy is superior to thoracotomy lobectomy. We screened 17,923 studies. After independent review of the abstracts by 2 reviewers, we included 39 studies (only one randomized controlled trial) in our analysis. In aggregate, these 39 studies involved 3256 thoracotomy and 3114 VATS patients. The characteristics of the two groups were not significantly different. Compared with thoracotomy, VATS lobectomy was associated with shorter chest tube duration, shorter length of hospital stay, and improved survival (at 4 years after resection), all statistically significant. Compared with lobectomy performed by thoracotomy, VATS lobectomy for patients with early-stage NSCLC is appears to favor lower morbidity and improved survival rates.

The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups

OBJECTIVE Lung cancer is the leading cause of cancer death in North America. Low-dose computed tomography screening can reduce lung cancer-specific mortality by 20%. METHOD The American Association for Thoracic Surgery created a multispecialty task force to create screening guidelines for groups at high risk of developing lung cancer and survivors of previous lung cancer. RESULTS The American Association for Thoracic Surgery guidelines call for annual lung cancer screening with low-dose computed tomography screening for North Americans from age 55 to 79 years with a 30 pack-year history of smoking. Long-term lung cancer survivors should have annual low-dose computed tomography to detect second primary lung cancer until the age of 79 years. Annual low-dose computed tomography lung cancer screening should be offered starting at age 50 years with a 20 pack-year history if there is an additional cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Lung cancer screening requires participation by a subspecialty-qualified team. The American Association for Thoracic Surgery will continue engagement with other specialty societies to refine future screening guidelines. CONCLUSIONS The American Association for Thoracic Surgery provides specific guidelines for lung cancer screening in North America.

MicroRNA expression profiles of esophageal cancer

OBJECTIVE Expression of microRNAs by array analysis provides unique profiles for classifying tissues and tumors. The purpose of our study was to examine microRNA expression in Barrett esophagus and esophageal cancer to identify potential markers for disease progression. METHODS MicroRNA was isolated from 35 frozen specimens (10 adenocarcinoma, 10 squamous cell carcinoma, 9 normal epithelium, 5 Barrett esophagus, and 1 high-grade dysplasia). MicroRNA expression was analyzed with Ambion bioarrays (Ambion, Austin, Tex) containing 328 human microRNA probes. RESULTS Unsupervised hierarchic clustering resulted in four major branches corresponding with four histologic groups. One branch consisted of 7 normal epithelium samples and 1 squamous cell carcinoma sample. The second branch consisted of 7 squamous cell carcinoma samples and 1 normal epithelium sample. The third branch contained 4 Barrett esophagus samples and 1 squamous cell carcinoma sample. The fourth contained all the adenocarcinoma samples and 1 sample each of Barrett esophagus, normal epithelium, squamous cell carcinoma, and high-grade dysplasia. Supervised classification with principal component analysis determined that the normal epithelium samples were more similar to the squamous cell carcinoma tumors, whereas the Barrett esophagus samples were more similar to adenocarcinoma. Pairwise comparisons between sample types revealed microRNAs that may be markers of tumor progression. Both mir_203 and mir_205 were expressed 2- to 10-fold lower in squamous cell carcinoma and adenocarcinomas than in normal epithelium. The mir_21 expression was 3- to 5-fold higher in both tumors than in normal epithelium. Prediction analysis of microarray classified 3 Barrett esophagus samples as Barrett esophagus, 1 as adenocarcinoma, and 1 as normal epithelium. CONCLUSION Expression profiles of miRNA distinguish esophageal tumor histology and can discriminate normal tissue from tumor. MicroRNA expression may prove useful for identifying patients with Barrett esophagus at high risk for progression to adenocarcinoma.

Video-Assisted Thoracic Surgery Lobectomy: Report of CALGB 39802—A Prospective, Multi-Institution Feasibility Study

PURPOSE To evaluate the technical feasibility and safety of video-assisted thoracic surgery (VATS) lobectomy for small lung cancers. PATIENTS AND METHODS The Cancer and Leukemia Group B 39802 trial was a prospective, multi-institutional study designed to elucidate the technical feasibility of VATS in early non-small-cell lung cancer (NSCLC) using a standard definition for VATS lobectomy (one 4- to 8-cm access and two 0.5-cm port incisions) that mandated videoscopic guidance and a traditional hilar dissection without rib spreading. Between 1998 and 2001, 128 patients with peripheral lung nodules < or = 3 cm in size with suspected NSCLC were prospectively registered for VATS lobectomy. RESULTS One hundred twenty-seven patients (66 males and 61 females; median age, 66 years; range, 37 to 86 years), with a performance status of 0 (74%) or 1 (26%), underwent surgery. Patients with lymph nodes more than 1 cm by computed tomography scan underwent mediastinal lymph node sampling to rule out N2 disease. One hundred eleven patients (87%) had stage I lung cancer, and 96 (86.5%) of these 111 patients underwent successful VATS lobectomies. The median procedure length was 130 minutes (range, 47 to 428 minutes), and median chest tube duration was 3 days (range, 1 to 14 days). Fifty-eight (60%) of 97 patients underwent diagnostic biopsy at lobectomy. Within 30 days, three (2.7%) of 111 patient deaths occurred, none of which were directly related to VATS technique; seven (7.4%) of 95 patients had grade 3 or greater complications, with only one case of bleeding. CONCLUSION A standardized approach to VATS lobectomy as specifically defined with avoidance of rib spreading is feasible.

Sustained activation of vascular cells and leukocytes in the rabbit aorta after balloon injury.

BackgroundTo improve understanding of the cellular basis of the arterial response to injury, we tested whether balloon withdrawal can induce certain inflammatory functions of vascular cells and leukocytes and whether such “activation” persists even after the acute phase of injury. Methods and ResultsWe examined the expression of several inducible cell surface molecules in the rabbit aorta at 2, 5, 10, and 30 days after balloon injury. Longitudinal sections encompassing parts of the uninjured, border, and injured zones were examined for expression of vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-i (ICAM-1), class II major histocompatibility (MHC) antigens, and markers for smooth muscle cells (SMCs), macrophages, endothelial cells, and T-lymphocytes. Endothelial cell healing involved true endothelial regeneration as well as migration, as shown by nuclear incorporation of bromodeoxyuridine. Luminal endothelial cells at the leading edge of repopulation at each time point expressed VCAM-1. As healing progressed, VCAM-1 expression decreased in the regenerated endothelial cells. The neointimal endothelium also expressed high levels of ICAM-1 that persisted longer than the elevation of VCAM-1. SMCs in the neointima also showed increased levels of ICAM-1. Some neointimal endothelial cells, SMCs, and macrophages also expressed high levels of class II MHC antigens during 30 days after injury ConclusionsLocal inflammatory activation of endothelial cells, SMCs, and leukocytes occurs in a predictable sequence and persists up to 30 days after balloon injury to the rabbit aorta. Our findings suggest that ongoing local signals persisting after the original balloon injury may contribute to later phases of intimal thickening.

Patterns of Failure After Trimodality Therapy for Malignant Pleural Mesothelioma

BACKGROUND Malignant pleural mesothelioma is uncommon, and presently, no standard treatment of this disease exists. The objective of our analysis was to study the patterns of failure for malignant pleural mesothelioma after trimodality treatment consisting of extrapleural pneumonectomy, chemotherapy, and radiation therapy. METHODS Between 1987 and 1993, 49 patients with malignant pleural mesothelioma underwent extrapleural pneumonectomy. There were two perioperative deaths, and 1 patient died 5 weeks after extrapleural pneumonectomy. Thirty-five of the surviving patients received adjuvant chemotherapy (32/35 received cyclophosphamide, doxorubicin, and cisplatin) followed by hemithorax radiation therapy. Ten patients received chemotherapy but no radiation therapy, and 1 patient received no adjuvant therapy. Median follow-up time for the 23 living patients from the date of operation was 18 months. RESULTS Of the 46 evaluable patients, 25 had recurrence (54%), with a median time to first failure of 19 months (range, 5 to 51 months). The sites of first recurrence were local in 35% of patients, abdominal in 26%, the contralateral thorax in 17%, and other distant sites in 8%. (Some patients had recurrence in multiple sites simultaneously.) CONCLUSIONS The most common site of failure after trimodality therapy was the ipsilateral hemithorax. Isolated distant failures were uncommon. Future strategies should investigate methods of enhancing local tumor control.

Vaccination With Irradiated Autologous Tumor Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Augments Antitumor Immunity in Some Patients With Metastatic Non–Small-Cell Lung Carcinoma

PURPOSE We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival

BACKGROUND This study was undertaken to determine the predictive value of nodal status at resection in regards to long-term outcome of patients undergoing neoadjuvant therapy and resection for stage IIIA N2-positive non-small cell lung cancer (NSCLC). METHODS We reviewed the medical records of all patients found on surgical staging to have N2-positive NSCLC and who underwent induction therapy followed by resection between 1988 and 1996 at our hospital. Complete follow-up information was examined utilizing Kaplan-Meier survival analysis and Cox proportional hazards multivariate analysis. RESULTS One hundred three patients (59 men) with stage IIIA N2-positive NSCLC received neoadjuvant therapy before surgical resection. Preoperative therapy consisted of platinum-based chemotherapy (76), radiotherapy (18), or chemoradiation (9). Operations included pneumonectomy (38), bilobectomy (6), and lobectomy (59). There were four deaths and seven major complications. Eighty-five patients were followed until death. Median survival among 18 living patients is 60.9 months (range 29 to 121 months). Twenty-nine patients were downstaged to N0 and had 5-year survival of 35.8% (median survival 21.3 months). Seventy-four patients with persistent tumor in their lymph nodes (25 N1 and 49 N2) had significantly worse, 9%, 5-year survival, p = 0.023 (median survival 15.9 months). Other negative prognostic factors were adenocarcinoma and pneumonectomy. CONCLUSIONS Patients with N2-positive NSCLC whose nodal disease is eradicated after neoadjuvant therapy and surgery enjoy significantly improved cancer-free survival. These data support surgical resection for patients downstaged by induction therapy; however, patients who are not downstaged do not benefit from surgical resection. Direct effort should be made to improve the accuracy of restaging before resection.

Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients.

OBJECTIVE The authors examine the feasibility and efficacy of trimodality therapy in the treatment of malignant pleural mesothelioma and identify prognostic factors. BACKGROUND Mesothelioma is a rare, uniformly fatal disease that has increased in incidence in recent decades. Single and bimodality therapies do not improve survival. METHODS From 1980 to 1995, 120 patients underwent treatment for pathologically confirmed malignant mesothelioma at Brigham and Womens Hospital and Dana-Farber Cancer Institute (Boston, MA). Initial patient evaluation was performed by a multimodality team. Patients meeting selection criteria and with resectable disease identified by computed tomography scan or magnetic resonance imaging underwent extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy. RESULTS The cohort included 27 women and 93 men with a mean age of 56 years. Operative mortality rate was 5.0%, with a major morbidity rate of 22%. Overall survival rates were 45% at 2 years and 22% at 5 years. Two and 5-year survival rates were 65% and 27%, respectively, for patients with epithelial cell type, and 20% and 0%, respectively, for patients with sarcomatous or mixed histology tumors. Nodal involvement was a significant negative prognostic factor. Patients who were node negative with epithelial histology had 2- and 5-year survival rates of 74% and 39%, respectively. Involvement of margins at time of resection did not affect survival, except in the case of full-thickness, transdiaphragmatic invasion. Classification on the basis of a revised staging system stratified median survivals, which were 22, 17, and 11 months for stages I, II, and III, respectively (p = 0.04). CONCLUSIONS Extrapleural pneumonectomy with adjuvant therapy is appropriate treatment for selected patients with malignant mesothelioma selected using a revised staging system.