Jeanne M. Lukanich

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.

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.

Transthoracic esophagectomy with radical mediastinal and abdominal lymph node dissection and cervical esophagogastrostomy for esophageal carcinoma

BACKGROUND Several techniques for esophageal resection have been reported. This study examines the morbidity, mortality, and early survival of patients after transthoracic esophagectomy for esophageal carcinoma using current staging techniques and neoadjuvant therapy. The technique includes right thoracotomy, laparotomy, and cervical esophagogastrostomy (total thoracic esophagectomy) with radical mediastinal and abdominal lymph node dissection. METHODS Three hundred forty-two patients had surgery for esophageal carcinoma between 1989 and 2000 at our institution. Two hundred fifty consecutive patients had esophagectomy using this technique. Kaplan-Meier curves and univariate and multivariate analyses were performed by postsurgical pathologic stage. RESULTS Median age was 62.7 years (31 to 86 years). Fifty-nine were female. Eighty-one percent (202) had induction chemotherapy (all patients with clinical T3/4 or N1). Early postoperative complications included recurrent laryngeal nerve injury (14% [35]), chylothorax (9%, [22]), and leak (8%, [19]). Median length of stay was 13 days (5 to 330 days). In-hospital or 30-day mortality was 3.6% (9). Overall survival at 3 years was 44%; median survival was 25 months, and 3-year survival by posttreatment pathologic stage was: stage 0 (complete response) (n = 60), 56%; stage I (n = 32), 65%; stage IIA (n = 67), 41%; stage IIB (n = 30), 46%; and stage III (n = 49), 17%. Mean follow-up was 24 months (SEM 1.6, 0 to 138 months). Five patients with tumor in situ, 6 patients with stage IV disease, and 1 patient who could not be staged (12 pts) were excluded from survival and multivariate calculations. In univariate and different models of multivariate analysis, age more than 65 years, posttreatment T3, and nodal involvement were predictive of poor survival. For univariate analysis, p = 0.002, p = 0.004, p = 0.02, respectively; for multivariate analysis, p = 0.001, p = 0.003, p = 0.02, respectively. CONCLUSIONS Total thoracic esophagectomy with node dissection for esophageal cancer appears to have acceptable morbidity and mortality with encouraging survival results in the setting of neoadjuvant therapy. Patients who show complete response after induction chemoradiotherapy appear to have improved long-term survival.

High Risk of Brain Metastases in Surgically Staged IIIA Non–Small-Cell Lung Cancer Patients Treated With Surgery, Chemotherapy, and Radiation

PURPOSE Lung cancer is the leading cause of cancer mortality in the United States. We sought to review our experience with surgically staged IIIA (N2) non-small-cell lung cancer (NSCLC), focusing on the patterns of failure in consecutively treated patients from 1988 to 2000. PATIENTS AND METHODS The records of 177 patients were reviewed. Collected data included stage, histology, use of chemotherapy and radiation, initial and subsequent sites of failure, and survival. One hundred twenty-four patients have died; follow-up time is 35 months among the remaining patients. RESULTS The median survival from the time of surgery was 21.0 months, with a 3-year overall survival (OS) of 34%. Nodal downstaging to N0 disease correlated with OS and progression-free survival (PFS; P < .001). The most common site of recurrence was the brain. Thirty-four percent of patients recurred in the brain as their first site of failure, and 40% of patients developed brain metastases at some point in their course. In patients with nonsquamous histology and residual nodal involvement after neoadjuvant therapy, the risk of brain metastases was 53% at 3 years. CONCLUSION Patients treated with neoadjuvant therapy for N2-positive stage IIIA NSCLC enjoy an advantage in both OS and PFS if their lymph node status is downstaged to N(0). Because brain metastases constitute the most common site of failure in these patients, future studies focusing on prophylaxis of brain metastases may improve the outcome in patients with stage IIIA NSCLC.

Smoking cessation is challenging even for patients recovering from lung cancer surgery with curative intent

BACKGROUND Although it is recommended that smokers undergoing surgery for lung cancer quit smoking to reduce post-operative complications, few studies have examined patterns of smoking in the peri-operative period. The goals of this study were to determine: (1) patterns of smoking during post-operative recovery, (2) types of cessation strategies used to quit smoking, and (3) factors related to smoking after lung cancer surgery. METHODS Data were collected from 94 patients through chart review, tobacco, health status, and symptom questionnaires at 1, 2, and 4 months after surgery. Smoking status was assessed through self-report and urinary cotinine measurement. RESULTS Eighty-four patients (89%) were ever-smokers and 35 (37%) reported smoking at diagnosis. Thirty-nine (46%) ever-smokers remained abstinent, 13 (16%) continued smoking at all time-points, and 32 (38%) relapsed. Ten (46%) of those who relapsed were former-smokers and had not smoked for at least 1 year. Sixteen (46%) of those who were smoking at diagnosis received cessation assistance with pharmacotherapy being the most common strategy. Factors associated with smoking during recovery were younger age and quitting smoking < or =6 months before the diagnosis of lung cancer. Factors that were marginally significant were lower educational level, male gender, lower number of comorbidities, and the presence of pain. CONCLUSION Only half of those who were smoking received assistance to quit prior to surgery. Some patients were unable to quit and relapse rates post-surgery were high even among those who quit more than 1 year prior. Innovative programs incorporating symptom management and relapse prevention may enhance smoking abstinence during post-operative care.

Experience with repair of congenital heart defects using adjunctive endovascular devices

The use of endovascular devices as an adjunct to repair of congenital heart anomalies represents a novel but unproven therapeutic approach. Intraoperative implantation of pulmonary arterial stents (5 to 15 mm diameter) was done in 11 patients with pulmonary atresia with ventricular septal defect (n = 4), classic tetralogy of Fallot (n = 2), truncus arteriosus (n = 1), hypoplastic left heart syndrome (stage II [n = 1] and stage III [n = 1] Norwood procedure), and miscellaneous pulmonary arterial stenoses (n = 3), as well as in patients with congenital (n = 1) and postoperative (n = 3) pulmonary venous obstruction and in 1 patient with combined pulmonary arterial and venous obstruction. The stents were effective at achieving immediate patency in all patients. There were two early deaths, one related to acute thrombosis of a small-diameter left pulmonary artery stent. Reintervention because of stent-related pulmonary arterial stenosis was frequently necessary. In five of seven patients who survived more than 1 month after implantation of stent size 8 mm or smaller severe stent-related pulmonary arterial obstruction developed. In four of the five patients with pulmonary vein stent implantation intractable obstruction developed, resulting in death in all three patients who had bilateral pulmonary vein stent implantation. Intraoperative occlusion of apical muscular ventricular septal defect with use of a clamshell device inserted from the right atrial approach was accomplished in four patients. One patient who underwent associated aortic arch reconstruction died as a result of left ventricular hypoplasia. The results in the remaining three patients were favorable on the basis of absence of significant late residual intraventricular shunting, left ventricular dysfunction, or arrhythmia. We conclude that recurrent intraluminal obstruction as a result of neointimal hyperplasia appears to be an eventual certainty in currently designed small-diameter endovascular stents. For this reason, we would recommend standard surgical techniques for repair of obstructive lesions of the pulmonary arterial confluence to maximize growth potential. Device occlusion of muscular ventricular septal defects is feasible but probably only indicated for complex cases of ventricular septal deficiency that otherwise necessitate a left ventriculotomy.

Menopausal effects on presentation, treatment, and survival of women with non-small cell lung cancer

BACKGROUND Small population studies have reported higher survival rates for women than men with non-small cell lung carcinoma (NSCLC). Because human NSCLC cells express estrogen receptors, we evaluated hormonally active and inactive women to identify biologically mediated differences. METHODS A total of 14,676 US women with stage I through IV primary non-small cell lung cancer (NSCLC) from the 1992 to 1997 Surveillance, Epidemiology, and End Results database were grouped into two categories based on the average menopausal age of 51 years as defined by the American College of Obstetricians and Gynecologists: ages 31 to 50 premenopausal (n = 2,230, 15%) and ages 51 to 70 postmenopausal (n = 12,446, 85%). Extreme ages were excluded. Statistics were calculated with chi(2) or Mann-Whitney tests, Kaplan-Meier estimates with log-rank tests, and Cox proportional hazards models. RESULTS Premenopausal women more commonly presented with advanced clinical stage, less favorable histology (adenocarcinoma), and poorly differentiated tumors, and more often underwent pneumonectomies. Surgery with curative intent was performed in 31% premenopausal and 33% postmenopausal women (p = 0.03). Overall survival for premenopausal and postmenopausal women was not significantly different (median 10 and 9 months, all stages; 70 and 71 months, stages I and II). Adjusting for significant covariates (stage, histology, size, grade, extent of surgery), postmenopausal women had higher lung-cancer-related deaths (hazard ratio, 1.14; 95% confidence interval, 1.03 to 1.27). CONCLUSIONS Premenopausal women presented more often with advanced disease and underwent more extensive resection, yet had survival advantage after covariate adjustment. Additionally, postmenopausal women had a survival advantage compared with their male counterparts. Results suggest that estrogen exposure creates a milieu that may confer a protective effect through some yet unknown mechanisms that determine outcome of the neoplastic process and warrant further investigation.

Surveillance transbronchial lung biopsies: implication for survival after lung transplantation.

OBJECTIVES We wished to determine whether early rejection after lung transplantation as assessed by surveillance transbronchial biopsy predicts for survival. METHODS Between 1990 and 1997, 96 consecutive patients had lung transplantation: 89 had a minimum 1-month follow-up. For 71 consecutive patients we have 1-year follow-up and for 69 patients we have the results of the first 3 biopsies. Cytomegalovirus status, bronchiolitis obliterans prevalence, and use of total lymphoid irradiation are noted. Biopsies were done at 1 week and 1, 3, and 6 months. Standard immunosuppression consisted of induction antilymphocyte globulin and high-dose methylprednisolone induction for 1 week and standard maintenance triple therapy. Acute rejection treatment was with pulse methylprednisolone. Bronchiolitis obliterans syndrome was treated with total lymphoid irradiation and a change to tacrolimus and mycophenolate. Blinded grading using International Society for Heart and Lung Transplantation classification was done retrospectively. RESULTS Survival at 1 month and 1, 2, and 3 years for the 96-patient cohort with 1-year follow-up was 93%, 74%, 62%, and 56%. Survival was not significantly different for subsets with rejection on any combination of the first 3 biopsies (1/3, 2/3, 3/3) or absence of rejection on the first 3 biopsies. Ninety-one positive biopsy results were graded. Eighteen of 71 patients had one or more moderate or severe rejection episodes without survival difference relative to the others. There was no statistically significant association between acute rejection on the first 3 surveillance biopsy results and bronchiolitis obliterans. CONCLUSIONS Intensive induction and maintenance immunotherapy with surveillance transbronchial biopsies and aggressive treatment of acute rejection is associated with a survival similar to that of patients without early acute rejection. This regimen appears to uncouple the association between early acute rejection and bronchiolitis obliterans. Further study may elucidate this mechanism.

Gas Flow During Bronchoscopic Ablation Therapy Causes Gas Emboli to the Heart: A Comparative Animal Study

BACKGROUND Thermal ablation is one of the most commonly used modalities to treat central airway obstruction. Both laser and argon plasma coagulation (APC) have been reported to cause gas emboli and cardiac arrest. We sought to determine whether bronchoscopic ablation therapy can result in systemic gas emboli, correlate their presence with the rate of gas flow, and establish whether a zero-flow (ZF) modality would result in the significant reduction or elimination of emboli. METHODS CO(2) laser delivered through a photonic bandgap fiber (PBF) and APC were applied in the trachea and mainstem bronchi of six anesthetized sheep at varying dosages and gas flow rates. Direct epicardial echocardiography was used to obtain a four-chamber view and detect gas emboli. RESULTS The presence of gas flow accompanying APC and the CO(2) laser with forward flow correlated significantly with the appearance of gas bubbles in the atria. A definite dose response was observed between the gas flow rate and the number of bubbles seen. When the CO(2) laser was delivered through a PBF with ZF to the trachea or bronchi, no bubbles were observed. CONCLUSION Bronchoscopic thermal ablation therapy using gas flow is associated with gas emboli in a dose-dependent fashion. The use of the flexible PBF with ZF is not associated with the development of gas emboli. Further study is required to determine whether a clinically safe threshold of gas emboli exists, and the relationships among the pathologic depth of tissue destruction, gas flow, pulse duration, and the development of gas emboli.

Section I: Epidemiological review

The incidence of esophageal adenocarcinoma has increased tremendously in the United States and other Western countries over the past 30 years while the incidence of esophageal squamous cell carcinoma has remained unchanged. The rate of increase in incidence is higher than for any other cancer. The reasons for this are multifactorial. Despite this, esophageal cancer remains a relatively uncommon malignancy. Barretts esophagus (BE) is the most important risk factor for the development of esophageal adenocarcinoma and is believed to be the precursor lesion for most. The risk of developing esophageal adenocarcinoma from known BE is estimated to be 0.5% per patient year. Persistent high-grade dysplasia in BE is a sensitive indicator for the development of esophageal adenocarcinoma. However, only a minority of patients with BE are ever diagnosed and, therefore, surveillance endoscopy in Barretts patients has failed to affect the incidence of esophageal adenocarcinoma. The relationship of Helicobacter pylori to esophageal adenocarcinoma is complex, but nonsteroidal antiinflammatory drugs may confer protection against the development of this cancer. Fortunately, improved survival is being seen with both squamous cell esophageal carcinoma and esophageal adenocarcinoma. Additional study is required to better determine the risk factors for the development of esophageal cancer, and epidemiologic understanding will prove important in developing methods of detection and therapeutic intervention for this disease.