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The last two decades have seen an increasing search for in vitro models that can replace the use of animals for safety testing. We adapted the methods from a recent nonquantitative report of spermatogenesis occurring in ex vivo mouse testis explants and tried to develop them into a screening assay. The model consisted of small pieces of neonatal mouse testis (testis "chunks"), explanted and placed on pillars of agarose or chamber inserts, and cultured at the air-liquid interface. A peripheral torus-shaped zone in these explants would often contain tubules showing spermatogenesis, while the middle of each chunk was often necrotic, depending on the thickness of the tissue. The endpoint was histology: what proportion of tubules in the "permissive torus" actually contained healthy pachytene spermatocytes or spermatids? Extensive statistical modeling revealed that a useful predictive model required more than 60% of these tubules to show spermatogenesis. Separately, the logistics of running this as a predictive assay require that the controls consistently produce ≥ 60% tubules with pachytenes and round spermatids, and achieving this level of spermatogenesis reliably and consistently every week proved ultimately not possible. Extensive trials with various media additions and amendments proved incapable of maintaining the frequency of spermatogenic tubules at consistently ≥ 60%. Congruent with Schooler's "decline effect"; generally, the more often we ran these cultures, the worse the performance became. We hope that future efforts in this area may use our experience as a starting point on the way to a fully productive in vitro model of spermatogenesis.

Purpose/objectives To examine the demographic, medical, and social-cognitive correlates of adherence to a presurgical exercise training intervention in patients awaiting surgery for suspected malignant lung lesions. Design Pilot study, single-group, prospective design with convenience sampling. Setting Exercise training was performed at a university research fitness center in western Canada. Sample 19 patients awaiting surgical resection of suspected malignant lung lesions. Methods At baseline, participants completed a questionnaire including the Theory of Planned Behavior variables of perceived behavioral control, attitude, and subjective norm, as well as medical and demographic information. Participants were asked to attend five supervised exercise sessions per week during surgical wait time (X = 8 +/- 2.4 weeks). Main research variables Theory of Planned Behavior variables and exercise adherence. Findings Adherence to the exercise intervention was 73% (range = 0%-100%). Correlates of adherence were perceived behavioral control (r = 0.63; p = 0.004) and subjective norm (r = 0.51; p = 0.014). Participants with greater than 80% adherence reported significantly higher behavioral control than participants with less than 80% adherence (X difference = 1.1; 95% confidence interval = 0.1-2.2; p = 0.035). Men had better adherence than women (X difference = 24.9%; 95% confidence interval = 0.4-49.4; p = 0.047). Conclusions Perceived behavioral control and subjective norm were the strongest correlates of exercise adherence. Women could be at risk for poor exercise adherence prior to lung surgery. Implications for nursing This information could be useful for clinicians in their attempts to improve adherence to exercise interventions in patients awaiting surgery for malignant lung lesions.

Purpose p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non–small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. Methods p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. Results Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. Conclusion p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.

Purpose: High class III β-tubulin (bTubIII) expression in advanced non–small cell lung cancer is known to correlate with reduced response rates and inferior survival with anti-microtubule agents. JBR.10 showed a 12% and 15% improvement in 5-year recurrence-free survival (RFS) and overall survival (OS), respectively, with the addition of cisplatin and vinorelbine following resection of stage IB-II non–small cell lung cancer. We sought to determine the effect of bTubIII on patient outcome and benefit from adjuvant chemotherapy in the JBR.10 trial.Experimental Design: We did a semiquantitative immunohistochemical assay for bTubIII on primary tumor tissue available from 265 of the 482 patients in JBR.10. Tumors were classified as bTubIII “low” or “high” using a validated method. We examined the prognostic effect of bTubIII in patients treated with or without chemotherapy and the survival benefit from chemotherapy in low versus high bTubIII subgroups.Results: High bTubIII expression was associated with poorer RFS and OS in patients treated with surgery alone but not in patients treated with adjuvant chemotherapy. The RFS and OS benefits of adjuvant chemotherapy were greater in high versus low tubulin expressors. However, with Cox regression, the interaction between bTubIII status and chemotherapy treatment in predicting RFS or OS did not reach statistical significance.Conclusions: Chemotherapy seemed to overcome the negative prognostic effect of high bTubIII expression. Greater benefit from adjuvant chemotherapy was seen in patients with high bTubIII expression. This is contrary to what has been seen in the setting of advanced disease; possible reasons for this difference are being explored.

background We undertook to determine whether adjuvant vinorelbine plus cisplatin prolongs overall survival among patients with completely resected early-stage non–small-cell lung cancer. methods We randomly assigned patients with completely resected stage IB or stage II non–smallcell lung cancer to vinorelbine plus cisplatin or to observation. The primary end point was overall survival; principal secondary end points were recurrence-free survival and the toxicity and safety of the regimen. results A total of 482 patients underwent randomization to vinorelbine plus cisplatin (242 patients) or observation (240); 45 percent of the patients had pathological stage IB disease and 55 percent had stage II, and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. In both groups, the median age was 61 years, 65 percent were men, and 53 percent had adenocarcinomas. Chemotherapy caused neutropenia in 88 percent of patients (including grade 3 febrile neutropenia in 7 percent) and death from toxic effects in two patients (0.8 percent). Nonhematologic toxic effects of chemotherapy were fatigue (81 percent of patients), nausea (80 percent), anorexia (55 percent), vomiting (48 percent), neuropathy (48 percent), and constipation (47 percent), but severe (grade 3 or greater) toxic effects were uncommon (

Summary Resected non-small cell lung cancer (NSCLC) has 5-years survival rates of 30–70%. The role of adjuvant chemotherapy remains unclear with poor compliance reported in most trials. The compliance with adjuvant chemotherapy (ACT) for stage IB and II NSCLC was analyzed using data from a North American multi-centre phase III study (accrual 1994–2001) that compared adjuvant chemotherapy to observation. Planned chemotherapy consisted of cisplatin (CIS) 50mg/m 2 days 1, 8 and vinorelbine (VIN) 25mg/m 2 days 1, 8, 15, 22 for four cycles; the VIN dose had been reduced from 30mg/m 2 after an initial cohort of patients experienced unacceptable toxicity. Four hundred and twenty-four patients were randomized after the amendment, 215 to the chemotherapy arm. Median age was 60 years, 64% were male and 84% had stage II disease. Thirty-seven patients completed one cycle, 14 completed two, 20 completed three and 108 patients completed all four cycles. Ten patients received no therapy. Multivariate analysis demonstrated statistically significant differences in compliance with extent of surgery, gender and age. Patients randomized in Canada were more likely to fail to complete chemotherapy due to refusal of therapy than their American counterparts. Patients who had pneumonectomies were more likely to discontinue therapy due to toxicity than those who had lesser resections. Extent of surgery may play a role in both the compliance and toxicity of ACT. Differences between nations in the perception of the risks and benefits of adjuvant chemotherapy regimens, both between physicians and patients, should be investigated further.

We previously reported that our cDNA microarray analysis of primary non-small cell lung carcinoma (NSCLC) could predict for patients at increased risk of cancer recurrence. From the result of this analysis, we selected 11 genes that were considered candidate prognostic marker genes and used the realtime reverse transcription polymerase chain reaction (RT-PCR) to investigate their expression in the same set of NSCLC cases used in the microarray study. Cluster analysis of the realtime RT-PCR data separated these patients into two groups with significantly different disease-free survivals (log-rank test, P < 0.017). In contrast, cluster analysis failed to confirm the prognostic significance of the realtime RT-PCR results for these 11 genes in a validation series of 92 NSCLC cases. In univariate analysis, hypoxia inducible factor 1alpha, Rho-GDP dissociation inhibitor (GDI) alpha (RhoGDI) and Citron/rho-interacting serine-threonine kinase 21 (Citron K21) were significant prognostic factors for disease-free survival in the entire cohort of 130 NSCLC patients, but none were significant in multivariate analysis. The results demonstrate that the prognostic significance of microarray (SAM) results can be partially validated using realtime RT-PCR, but secondary validation using larger and independent series of tumors is necessary to identify true prognostic marker genes.

Purpose: Skp2 plays a critical role in cell cycle progression, especially at the G1-S transition, putatively through its control of several cell cycle regulator proteins. The Skp2 gene is located on a region of chromosome 5p that is commonly overrepresented in lung cancer. The present study aimed to evaluate Skp2 abnormalities and their prognostic value in non-small cell lung cancer (NSCLC). Experimental Design: In total 16 NSCLC cell lines and 163 primary tumors were included in studies to measure Skp2 relative gene copy number, mRNA abundance, and protein level. The tumors were also evaluated for p27 protein expression level and ras mutation. These values were correlated with the clinical and pathological features of the patients. Results: Skp2 relative gene copy number aberrations were found in 88 and 65% of NSCLC cell lines and primary tumors, respectively. Overrepresentation was especially common among squamous cell carcinoma (74%). Both gene copy overrepresentation (13%) and loss (35%) were found in adenocarcinoma. Skp2 relative gene copy number was significantly correlated with mRNA and protein levels, but none of these were correlated with p27 protein levels. Neither high Skp2 protein expression nor ras mutation was prognostically significant. In NSCLCs with ras mutation, however, high Skp2 protein expression was a significant independent poor prognostic marker. Conclusion: There appears to be a synergistic interaction between high Skp2 protein expression and ras mutation with negative impact on the survival of NSCLC patients.

Objective: The rate of complete resection (50%) and the 5-year survival (30%) for non–small cell lung carcinomas of the superior sulcus have not changed for 40 years. Recently, combined modality therapy has improved outcome in other subsets of locally advanced non–small cell lung carcinoma. This trial tested the feasibility of induction chemoradiation and surgical resection in non–small cell lung carcinoma of the superior sulcus with the ultimate aim of improving resectability and survival. Methods: Patients with mediastinoscopy-negative T3-4 N0-1 superior sulcus non–small cell lung carcinoma received 2 cycles of cisplatin and etoposide chemotherapy concurrent with 45 Gy of radiation. Patients with stable or responding disease underwent thoracotomy 3 to 5 weeks later. All patients received 2 more cycles of chemotherapy and were followed up by serial radiographs and scans. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed for significance by Cox regression analysis. Results: From April 1995 to September 1999, 111 eligible patients (77 men, 34 women) were entered in the study, including 80 (72.1%) with T3 and 31 with T4 tumors. Induction therapy was completed as planned in 102 (92%) patients. There were 3 treatment-related deaths (2.7%). Cytopenia was the main grade 3 to 4 toxicity. Of 95 patients eligible for surgery, 83 underwent thoracotomy, 2 (2.4%) died postoperatively, and 76 (92%) had a complete resection. Fifty-four (65%) thoracotomy specimens showed either a pathologic complete response or minimal microscopic disease. The 2-year survival was 55% for all eligible patients and 70% for patients who had a complete resection. To date, survival is not significantly influenced by patient sex, T status, or pathologic response. Conclusions: (1) This combined modality treatment is feasible in a multi-institutional setting; (2) the pathologic complete response rates were high; and (3) resectability and overall survival were improved compared with historical experience, especially for T4 tumors, which usually have a grim prognosis. (J Thorac Cardiovasc Surg 2001;121:472-83)

Background . In patients with apparently operable non-small cell lung cancer (NSCLC), clinicians often omit investigation for M disease in asymptomatic patients. Previous investigations have not specified in detail what is meant by "symptomatic," and this could differ between surgeons. We have investigated the extent to which surgeons' criteria differ for presence of symptoms. Methods . Participating surgeons from seven centers, enrolled patients they judged "asymptomatic" in a randomized trial of investigational strategies for NSCLC. Patients completed a structured questionnaire describing symptoms of the central nervous system (CNS). In 685 patients, we documented CNS symptom recurrence after resectional surgery over 1 year of follow-up. Results . Two centers enrolled only patients without even the mildest symptoms. Three centers took an intermediate approach, occasionally classifying patients with mild symptoms as "asymptomatic" and thus enrolling them in the trial. Two centers classified an appreciable number of patients with minimal symptoms, and occasionally with more than minimal symptoms, as "asymptomatic." Patients with even mild CNS symptoms were more likely to subsequently present with CNS metastases. Conclusions . Thoracic surgeons differ in their ideas of what may constitute the symptoms of M disease. Patients with structured questionnaire results that suggest symptoms of CNS disease are more likely to have CNS symptom recurrence after resectional surgery.

Methods: We have reviewed our experience in 38 patients with adenoid cystic carcinoma of the upper airway seen between 1963 and 1995. The mean age was 44.8 years (15 to 80 years) with a male/female ratio of 1:1.1. Thirty-two of the 38 patients were treated by resection and reconstruction (primary anastomosis 28; Marlex mesh prosthesis 4). Twenty-six of the 32 patients undergoing resection received adjuvant radiotherapy. Six patients with unresectable tumors were treated primarily with radiotherapy only. Results: Pathologic examination revealed local invasion beyond the wall of the trachea in all patients. In a majority, microscopic extension was found in submucosal and perineural lymphatics, well beyond the grossly visible or palpable limits of the tumor. Lymphatic metastases were relatively uncommon, occurring in only five of 32 (19%) patients undergoing resection. Metachronous hematogenous metastases occurred in 17 of 38 patients (44%). Thirteen of these 38 patients (33%) had pulmonary metastases. Sixteen of 32 resections were complete and potentially curative. There were two deaths within 30 days of operation. The mean survival in the 14 patients undergoing complete resection was 9.8 years (12 months to 29 years). Sixteen of 32 resections were incomplete (residual tumor at the airway margin on final pathologic examination), with one operative death occurring in this group. The mean survival in the 15 surviving patients was 7.5 years (4 months to 21 years). Six patients were treated with primary radiation only and had a mean survival of 6.2 years (2 months to 14.3 years). In the patients with pulmonary metastases, mean survival was 37 months (4 months to 7 years) from the time of diagnosis of the pulmonary metastasis until their death. Conclusion: Adenoid cystic carcinoma of the upper airway is a rare tumor, which is locally invasive and frequently amenable to resection. Although late local recurrence after resection is a feature of this tumor (up to 29 years), excellent long-term palliation is commonly achieved after both complete and incomplete resection. There was a small difference in survival between patients having complete and incomplete resection. Long periods of control can be obtained with radiotherapy alone. The best results, in this series of patients, were obtained by resection. Adjuvant radiotherapy is assumed to favorably influence survival. (J Thorac Cardiovasc Surg 1996;112:1522-32)

We reviewed all tissue specimens from 163 transplant patients (108 double lung transplant [DLT], 55 single lung transplant [SLT]) between November 1983 and January 1994 for abnormalities indicating bronchiolitis obliterans organizing pneumonia (BOOP) and found 17 cases (14 DLT and 3 SLT). Of the three SLTs, BOOP was diagnosed by open lung biopsy (OLB) in two and one was found at autopsy. Of the 14 DLTs, BOOP was diagnosed by transbronchial biopsy (TBB) specimens (9), OLB specimens (2), autopsy (1), TBB and OLB specimens (1), and OLB specimens and autopsy (1). BOOP was found between 1 and 43 months posttransplantation; time of survival from diagnosis was between 2 and 36 months with 9 patients presently alive. Concurrent pathologic diagnosis at the time of BOOP findings were as follows: acute rejection (7) (grade 1 [4] and grade 2 [3]), BO and grade 1 rejection (2), BO and grade 2 rejection (2), BO and Aspergillus infection (1), acute alveolar injury (1), acute alveolar injury and pulmonary embolus (1), acute rejection (grade 1) and Burkholderia cepacia pneumonia (1). No other pathologic diagnosis was found in 1 patient. In total, 11 of 17 patients (65%) had associated acute rejection. Of the 17 patients, 7 subsequently developed BO and 3 had BO before the finding of BOOP. Death occurred in 8 patients (5 DLT and the 3 SLT) between 2 and 6 months after the diagnosis. We conclude that BOOP is an important complication after lung transplantation; it was present in 13% of DLTs and 5% of SLTs. BOOP was most often associated with acute rejection.

Hypoxic pulmonary vasoconstriction (HPV) has not been demonstrated in human single lung anaesthesia in the lateral decubitus position (LDP). The purpose of this study was to determine whether (1) HPV occurs in the non-dependent, non-ventilated lung, and (2) if the infusion of sodium nitroprusside (SNP) inhibits HPV. During intravenous anaesthesia the tracheas of seven patients were intubated with double lumen endotracheal tubes. Standard monitors plus radial and pulmonary arterial catheters were placed. Patients were positioned in the LDP and haemodynamic and gas exchange data were recorded for each of three stages; I: two-lung ventilation, II: single, dependent lung ventilation (1 LV) and III: 1LV with infusion of SNP. In stage II the PaO2 decreased from 531 +/- 42 mmHg to 285 +/- 42 mmHg (P0.05) and Qs/Qt increased from 12.3 +/- 2.7 to 29.0 +/- 6.3% (P0.05). With SNP infusion there was a 30% increase in cardiac index (CI) (P0.05). The SNP infusion was not associated with changes in Qs/Qt or PaO2. This model demonstrates changes in Qs/Qt and PaO2 associated with single-lung ventilation in ASA I and II patients in the LDP but we were unable to demonstrate inhibition of HPV by SNP.

Cardiopulmonary bypass has been widely used in the management of isolated single and double lung transplantations. Although there are certain clear-cut preoperative indications for cardiopulmonary bypass, in many patients the decision to use this modality is based on the hemodynamic consequences of intraoperative pulmonary artery clamping. We have performed 109 isolated lung transplantations. In 69 patients (38 single lung transplantations and 31 double lung transplantations) cardiopulmonary bypass was initiated only on the basis of intraoperative hemodynamics. We have analyzed preoperative data From these 69 patients to determine whether an intraoperative requirement for cardiopulmonary bypass can be predicted. Of 38 single lung transplantations, 12 necessitated cardiopulmonary bypass (all patients had restrictive lung disease). No patients with obstructive lung disease who underwent single lung transplantation required cardiopulmonary bypass (p

Between November 1983 and March 1991, we performed 50 single and 40 double lung transplants in 82 recipients. Early deaths occurred in six (13 %) single and in eight (21 %) double lung transplant recipients. Late deaths occurred in 11 (28%) single and in one (3%) double lung recipients. Twenty-three of 37 (62%) single and 17 of 24 (71%) double lung transplant recipients have survived at least 1 year after the operation. In patients surviving at least 3 months after the operation (36 of 47 single lung transplant [77%] and 28 of 37 double lung transplant recipients [76%]), significant improvement occurred in arterial blood gases, pulmonary function tests, and exercise capacity. During our initial experience, airway anastomotic complications were the main cause of early morbidity and mortality. With newer surgical techniques and improved perioperative care, airway complications are now uncommon. Infectious complications, either bacterial (Pseudomonas cepacia) or viral (cytomegalovirus), are now the main cause of early mortality. Chronic rejection in the form of obliterate bronchiolitis has become a frequent cause of late morbidity. (J T horac C ardiovasc S urg 1992;103:295—306)

Between March 1988 and March 1991, 17 patients underwent bilateral lung transplantation for end-stage lung disease caused by cystic fibrosis. There were 11 male and six female patients. Ages ranged from 19 to 41 years (mean age 28 years). Preoperative mean arterial oxygen tension with the patient breathing room air was 54 +/- 6 mm Hg; forced vital capacity, 1.8 +/- 0.7 L; forced expiratory volume in 1 second, 0.9 +/- 0.3 L; and 6-minute walk test, 506 +/- 44 m. Immunosuppression consisted of cyclosporine, azathioprine, and prednisone. Induction immunosuppression was obtained with Minnesota antilymphocyte globulin. All patients received perioperative antibiotics according to sputum cultures and sensitivities. There were six operative deaths, four of which resulted from bacterial infection. Two patients required a second transplantation, one receiving a single lung and one undergoing bilateral lung replacement. Significant functional improvement was observed in all survivors. At 3 months follow-up, mean arterial oxygen tension on room air was 95 +/- 6 mm Hg (p less than 0.01); forced vital capacity, 3 +/- 0.8 L (p less than 0.01); forced expiratory volume in 1 second, 2.6 +/- 0.9 L (p less than 0.01); and 6-minute walk test, 678 +/- 47 m (p less than 0.01). The actuarial survival rate was 66% at 3 months and 58% at 6, 12, and 24 months. The most frequent cause of morbidity and mortality was acute pneumonia resulting from Pseudomonas cepacia. For patients with respiratory failure caused by cystic fibrosis, bilateral lung transplantation is an effective treatment option associated with significant functional improvement.

The aim of this study was to explore the effects of presurgical exercise training on quality of life (QOL) in patients with malignant lung lesions. Using a single-group prospective design, patients were enrolled in supervised aerobic exercise training for the duration of surgical wait time (mean 59.7 days). Participants completed assessments of cardiorespiratory fitness (peak oxygen consumption) and QOL using the Functional Assessment of Cancer Therapy-Lung scales, including the trial outcome index (TOI) and the lung cancer subscale (LCS) at baseline, immediately presurgery, and postsurgery (mean, 57 days). 9 participants provided complete data. Repeated-measures analysis indicated a significant effect for time on TOI (P = .006) and LCS (P = .009). Paired analysis revealed that QOL was unchanged after exercise training (ie, baseline to presurgery), but there were significant and clinically meaningful declines from presurgery to postsurgery in the LCS (-3.6, P = .021) and TOI (-8.3, P = .018). Change in peak oxygen consumption from presurgery to postsurgery was significantly associated with change in the LCS (r = 0.70, P = .036) and TOI (r = 0.70, P = .035). Exercise training did not improve QOL from baseline to presurgery. Significant declines in QOL after surgery seem to be related to declines in cardiorespiratory fitness. A randomized controlled trial is needed to further investigate these relationships.

Combined modality treatment with chemotherapy and radiation produces tumor regression in most patients with small-cell lung cancer, but the impact on survival has been small, and less than 20% of patients with limited disease survive 2 years. Survival time is extremely short after failure to respond or relapse after treatment. Local control remains a problem, with one third of patients having recurrence only at the primary site. In an attempt to prolong survival and perhaps achieve cure, we undertook surgical resection in 28 patients with limited small-cell lung cancer who did not have complete remission with standard treatment or who had only local recurrence after treatment. There were 28 patients, 22 male and six female, median age 61 years (range 41 to 76). All patients had been treated with chemotherapy and 13 had received preoperative radiotherapy to the primary site and mediastinum. Eight patients underwent an operation for relapse after complete remission. Five patients had had no response to treatment, three had had a slight response followed by progression during chemotherapy, and 12 had achieved partial response but had greater than 3 cm residual masses. Twelve patients required pneumonectomy, 15 lobectomy, one patient had unresectable disease, and two had bulky residual masses after the operation. Three others had microscopic residual disease. Pathologic examination showed only small-cell lung cancer in 18 patients, mixed small-cell and non-small-cell in four, and only non-small-cell lung cancer in six. There were only four patients with stage I disease, 10 with stage II, and 14 with stage III. The median survival from the date of diagnosis for the entire group is 105 weeks and from the date of operation, 74 weeks. The projected 5-year survival rate is 23%. The two patients with residual masses died with local progression, and distant metastatic disease developed in 17 others. One patient died at 6 years without recurrent disease. Eight patients are alive 2 to 5 years after diagnosis. Seven of these patients required only a lobectomy, four had stage I disease, two had stage II, and two had stage III disease. Five had pure small-cell lung cancer and three had mixed small-cell and non-small-cell tumors. All of the patients with pathologic stage I disease remain alive compared with one of 10 with stage II disease and two of 14 with stage III. In summary, relapse or failure to respond to chemotherapy may be due to non-small-cell lung cancer or a mixed tumor. A small number of patients with limited small-cell lung cancer without mediastinal node involvement may be cured by surgery after relapse or failure to respond to chemotherapy and radiotherapy.

Purpose Adjuvant chemotherapy for early stage non–small-cell lung cancer (NSCLC) is now the standard of care, but there is little information regarding its impact on quality of life (QOL). We report the QOL results of JBR.10, a North American, intergroup, randomized trial of adjuvant cisplatin and vinorelbine compared with observation in patients who have completely resected, stages IB to II NSCLC. Patients and Methods QOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a trial-specific checklist at baseline and at weeks 5 and 9 for those who received chemotherapy and at follow-up months 3, 6, 9, 12, 18, 24, 30 and 36. A 10-point change in QOL scores from baseline was considered clinically significant. Results Four hundred eighty-two patients were randomly assigned on JBR.10. A total of 173 patients (82% of the expected) in the observation arm and 186 (85% of expected) in the chemotherapy arm completed baseline QOL assessments. The two groups were comparable, with low global QOL scores and significant symptom burden, especially pain and fatigue, after thoracotomy. Changes in QOL during chemotherapy were relatively modest; fatigue, nausea, and vomiting worsened, but there was a reduction in pain and no change in global QOL. Patients in the observation arm showed considerable improvements in QOL by 3 months. QOL, except for symptoms of sensory neuropathy and hearing loss, in those treated with chemotherapy returned to baseline by 9 months. Conclusion The findings of this trial indicate that the negative effects of adjuvant chemotherapy on QOL appear to be temporary, and that improvements (with a return to baseline function) are likely in most patients.

Purpose This pooled analysis was undertaken to assess the efficacy and toxicity of adjuvant cisplatin-based chemotherapy in elderly patients with non–small-cell lung cancer (NSCLC). Methods We used individual patient data from 4,584 patients enrolled onto five trials of cisplatin-based chemotherapy who form the basis for the Lung Adjuvant Cisplatin Analysis (LACE) pooled analysis. Patient and treatment characteristics, overall and event-free survival, cause-specific mortality, chemotherapy toxicity and delivery were compared among three age groups: 3,269 young (71%; < 65), 901 midcategory (20%; 65 to 69), and 414 elderly patients (9%; ≥ 70). Log-rank tests stratified by trials were used with a test for trend to study the effect of chemotherapy on survival according to age. Results The hazard ratio (HR) of death for the young patients was 0.86 (95% CI, 0.78 to 0.94), 1.01 for the midcategory (95% CI, 0.85 to 1.21), and 0.90 for elderly patients (95% CI, 0.70 to 1.16; test for trend: P = .29). The HR for event-free survival was 0.82 for young (95% CI, 0.75 to 0.90), 0.90 for the midcategory (95% CI, 0.76 to 1.06), and 0.87 for elderly patients (95% CI, 0.68 to 1.11; test for trend: P = .42). More elderly patients died from non–lung cancer–related causes (12% young, 19% midcategory, 22% elderly; P < .0001). No differences in severe toxicity rates were observed. Elderly patients received significantly lower first and total cisplatin doses, and fewer chemotherapy cycles (χ2 P < .0001). Conclusion Adjuvant cisplatin-based chemotherapy should not be withheld from elderly patients with NSCLC purely on the basis of age.

We have had success with en bloc double lung transplantation in the management of selected patients with end-stage parenchymal pulmonary disease. Airway complications have been more prevalent in our own experience with double lung transplantation than in reports of combined heart-lung transplantation from other centers. Between November 1986 and March 1989, 16 patients underwent double lung transplantation. Allografts were preserved by topical hypothermic immersion in 12 patients and by pulmonary artery flush with cold crystalloid solution in the most recent four patients. Thirteen patients underwent tracheal anastomosis and the most recent three patients underwent bilateral bronchial anastomoses. Fatal ischemic necrosis of the donor trachea and both main bronchi developed in three patients. Preterminal airway ischemia developed in a patient who had systemic sepsis. Partial anastomotic dehiscence, which went on to form fibrous strictures necessitating endoscopic placement of silicone rubber airway stents, developed in two additional patients. Two other patients had late strictures and required subsequent placement of bifurcation stents. There was no relationship between development of airway complications and gas exchange in the donor lungs, lung ischemic time, early postoperative gas exchange, early postoperative mean pulmonary artery pressure, or frequency of early postoperative rejection. Severe postoperative hypotension occurred in five of eight patients with airway complications and in three of eight patients without airway complications.

Purpose National Cancer Institute of Canada Clinical Trials Group JBR.10 study is among the landmark trials that have established third generation platinum-based adjuvant chemotherapy as the standard of care after resection of stages IB-II NSCLC, improving absolute 5-year survival by 15% and median survival by 21 months. This cost-effectiveness analysis of adjuvant chemotherapy from the perspective of Canada's public health care system was undertaken based on the JBR.10 study population. Patients and Methods The primary outcome of the study was the incremental cost effectiveness ratio (ICER) expressed in dollars per life-year gained (LYG). Direct medical resource utilization data were collected retrospectively from trial data and medical records of patients enrolled in the JBR.10 study at the five largest accruing Canadian centers, from the time of random assignment until death or study closure (April 2004). Survival and available costs (2005 Canadian dollars [$CAD]) are presented both with and without discounting at 5% per year. Results Utilization data were collected from 172 Canadian patients (36% of the trial population), 85 randomly assigned to observation and 87 randomly assigned to chemotherapy. The mean costs of treatment per patient in the observation and adjuvant chemotherapy arms were $23,878 and $31,319, respectively, with an ICER of CAD$7,175/LYG discounted (95% CI, −$3,463 to $41,565), and $10,096/LYG undiscounted (95% CI, −$819 to $55,651). Conclusion Adjuvant vinorelbine plus cisplatin is a highly cost effective treatment that compares very favorably with other standard health care interventions.

Purpose Traditional treatment for superior sulcus non–small-cell lung cancers (SS NSCLC), radiation plus surgery, yields a 50% rate of complete resection and a 30% 5-year survival. On the basis of improved outcomes in other subsets of stage III NSCLC, this trial tested the feasibility of induction chemoradiotherapy for SS NSCLC. Patients and Methods Patients with T3-4, N0-1 SS NSCLC received two cycles of cisplatin and etoposide concurrently with radiation (45 Gy). Patients with stable or responding disease underwent thoracotomy. All patients received two more cycles of chemotherapy. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed by Cox regression analysis. Results From April 1995 to November 1999, 110 eligible patients (76 men, 34 women) were entered onto the study (78 T3, 32 T4 tumors). Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resection. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Pathologic CR led to better survival than when any residual disease was present (P = .02). Disease progression occurred mainly in distant sites. Conclusion This combined-modality approach is feasible and is associated with high rates of complete resection and pathologic CR in both T3 and T4 tumors. Local control and overall survival seem markedly improved relative to previous studies of radiation plus resection.

Background Rejection remains a significant cause of morbidity and mortality after lung transplantation. The purpose of this study was to test the efficacy and safety of daclizumab (DZM) vs anti-thymocyte globulin (ATG) as a component of induction therapy. Methods Fifty adults undergoing lung transplantation were randomized to receive either ATG or DZM during induction therapy. Patients were followed for 1 year after transplant. Results Although there was no significant difference in the number of acute or chronic rejections between groups, there was a trend toward a delay in time to first acute rejection with DZM induction. Average absolute lymphocytes and average platelet count were significantly higher in the DZM group. Cytomegalovirus (CMV) serology mismatch was higher in the DZM group (7 vs 1, p = 0.05). The DZM group had a greater number of infections (83 vs 47, p = 0.02); however, the number of CMV infections was also significantly greater (18 vs 6, p = 0.03), corresponding to a higher incidence of CMV mismatch. A cost analysis revealed no difference between total drug costs, intensive-care unit (ICU) costs and total hospital costs. One-year survival was 96% in the DZM group and 88% in the ATG group. Conclusions DZM is a safe component of induction therapy in lung transplantation. In addition, DZM may prolong freedom from acute rejection. Significant infections were more frequent in the DZM group, but this was likely due to a higher incidence of CMV mismatch. Both methods of induction therapy worked well, with excellent 1-year survival.

We report our experience with 2 cases of simultaneous single-lung transplantation and lung volume reduction for emphysema. The lung volume reduction was undertaken electively in an attempt to improve overall lung function above that to be expected from single-lung transplantation alone. There were no postoperative problems related to the addition of lung volume reduction. The pulmonary function at 3 months was greater than that seen in a retrospective group of bilateral lung transplants previously reported from our institution.

Skp2 plays a critical role in cell cycle progression, especially at the G(1)-S transition, putatively through its control of several cell cycle regulator proteins. The Skp2 gene is located on a region of chromosome 5p that is commonly overrepresented in lung cancer. The present study aimed to evaluate Skp2 abnormalities and their prognostic value in non-small cell lung cancer (NSCLC).In total 16 NSCLC cell lines and 163 primary tumors were included in studies to measure Skp2 relative gene copy number, mRNA abundance, and protein level. The tumors were also evaluated for p27 protein expression level and ras mutation. These values were correlated with the clinical and pathological features of the patients.Skp2 relative gene copy number aberrations were found in 88 and 65% of NSCLC cell lines and primary tumors, respectively. Overrepresentation was especially common among squamous cell carcinoma (74%). Both gene copy overrepresentation (13%) and loss (35%) were found in adenocarcinoma. Skp2 relative gene copy number was significantly correlated with mRNA and protein levels, but none of these were correlated with p27 protein levels. Neither high Skp2 protein expression nor ras mutation was prognostically significant. In NSCLCs with ras mutation, however, high Skp2 protein expression was a significant independent poor prognostic marker.There appears to be a synergistic interaction between high Skp2 protein expression and ras mutation with negative impact on the survival of NSCLC patients.

Recent studies have suggested that information from gene expression profiles could be used to develop molecular classifications of cancer. We hypothesized that expression levels of specific genes in operative specimens could be correlated to recurrence risk in non-small cell lung cancer (NSCLC). We performed expression profiling using 19.2 K cDNA microarrays on tumor specimens from a total of 39 NSCLC patients with known clinical follow-up information. Statistical analysis and clustering approaches were used to determine patterns of gene expression segregating with clinical outcome. The results provide evidence that molecular subtyping of NSCLC can identify distinct profiles of gene expression correlating with disease-free survival.

The purpose of this study was to describe the quality of life of patients who have received a transplant of the heart, liver, and lungs. We wished to document how the different patient groups fared in relation to each other with respect to physical, psychological, and social functioning, as well as in relation to published normative data. We also wished to identify factors that contribute to better functioning. We sent out a questionnaire by mail and received responses from 55 heart, 149 liver, and 59 lung transplant recipients (82% response rate). Measures included the SF-36, Mental Health Inventory, the State Anxiety Inventory, the UCLA Loneliness Scale-Revised, a quality of life measure that rated degree of improvement since transplantation, a measure of degree of difficulty in following medical and lifestyle regimens, sleep disturbance, and the Illness Intrusiveness Rating Scale. Results indicated that lung transplant patients reported better functioning than heart or liver transplant patients in all three domains of physical, psychological, and social functioning. Lung patients' level of functioning was equivalent to or better than published norms for the SF-36. Heart and liver recipients reported equivalent functioning to published norms in some domains, but reported impairment in the areas of physical and social functioning. Heart patients especially reported greater intrusiveness of their illness on their daily lives and indicated more difficulty complying with their lifestyle regimen. In all three groups, a large majority of patients reported feeling that life had improved since transplant with respect to health, energy level, activity level, and overall quality of life. Fewer patients reported improvements in the areas of sex life, marriage, family relationships, and social relationships. Where there were differences among the three patient groups, again it was the lung patients who reported more improvement in life since transplantation. Patients with better physical functioning tended to have more energy and pep, to be younger, to see themselves as being in better health, to feel less intrusion on their lives of their illness, and to be employed. Those with better psychological functioning tended to report less sleep disturbance, less loneliness, better social functioning, more vitality, and to be older. Better social functioning was associated with better mental health, less illness intrusiveness, and less role impairment as a result of physical or emotional factors. Relatively few patients-roughly a quarter of the total sample-reported that they were working either full or part time. We conclude that transplantation results in improved quality of life overall, but that problems persist for some patients in their physical and social functioning. Interventions aimed at improving rehabilitation in specific targeted areas may enable patients to resume a more fulfilling lifestyle posttransplant.

To investigate the clinical manifestations of Aspergillus infections in lung transplant recipients, we reviewed the mycology and autopsy reports of all double (DLT=93) and single (SLT=48) lung transplant recipients from November 1983 to May 1993. Positive Aspergillus cultures were identified in 22% of the recipients (DLT=21, SLT=10). Colonization alone was present in 19 recipients (DLT=16, SLT=3). Complicated Aspergillus infection included Aspergillus bronchitis (DLT=1, SLT=1), aspergilloma (SLT=2), pulmonary invasive aspergillosis (DLT=1, SLT=2), disseminated aspergillosis (DLT=1, SLT=2), empyema (DLT=1), and a retroperitoneal abscess (DLT=1). Symptoms were seen only in patients with complicated lung infections and CXR abnormalities began in the native lung of four SLT recipients. Twenty patients survived (DLT=17, SLT=3) and 11 died (DLT=4, SLT=7) of disseminated aspergillosis (SLT=2), pulmonary invasive disease (DLT=1), bronchiolitis obliterans (DLT=2, SLT=2, CMV pneumonitis (SLT=1), diffuse alveolar damage (SLT=2), and hyperacute rejection (DLT=1). Complicated infection and mortality were more common in SLTs than DLTs (P

It is common to assign an upper age limit for potential lung transplant recipients. The influence of age on LTX outcome is, however not, documented. A review of our first 103 LTXs, 51 single LTXs and 52 double LTXs, includes 31 recipients aged 50-63 years (mean 55.3 +/- 3.9); 19 received single LTX, and 12 received double LTX. Indications for LTX in those aged greater than 50 included proportionately more patients with emphysema and interstitial lung disease. Actuarial survivals in those aged less than 50 at 12, 36, and 60 months were 68%, 60%, and 55%, and in those aged greater than 50 was 70%, 61%, and 61%, respectively. The causes of death reflect a tendency of younger patients to die from graft rejection and older patients to die from sepsis. Acute rejection more than 6 weeks posttransplant and chronic rejection were less frequent in older patients (P < 0.05). The 6-minute walk and modified Bruce protocol tests, the incidence of CMV pneumonitis, and the late post-LTX renal function were not related to age. In conclusion, in carefully selected candidates in their sixth and seventh decades, LTX is an acceptable operation for end-stage lung disease. The tendency of older patients to a lower incidence of late allograft rejection (acute or chronic) may reflect decreased immunological responsiveness with age.

Twenty-four isolated double lung transplants (LTXs) have been performed in 22 patients with cystic fibrosis, with a follow-up of 4 to 47 months. Prior to LTX, all patients were colonized with Pseudomonas aeruginosa, and ten patients were also colonized with Pseudomonas cepacia. Both organisms were specifically sought before LTX. All patients who grew P cepacia before LTX did so after LTX. Five additional patients only grew this bacterium after LTX. There was no difference between those who grew P cepacia and those who did not in terms of data before LTX for age, weight, pulmonary function, and 6-min walk. After LTX, 7 of the 15 patients who had ever grown P cepacia died. No patient who grew only P aeruginosa died. The median survival in the subgroup with P cepacia was 28 days. Five of the seven died as a direct result of P cepacia pneumonia and sepsis. One died of cyclosporin A (cyclosporine) neurotoxicity with concurrent P cepacia pneumonia, and one died at the time of a retransplant for graft failure (associated with three bouts of P cepacia pneumonia and cytomegalovirus). Four of seven had not grown this bacterium before LTX. There were no perioperative factors, including antibiotic choices, that distinguished survivors and nonsurvivors. Overall 1-year survival is about 70 percent (15/22). Fourteen bouts of P cepacia pneumonia occurred in 12 patients. Four empyemas, one lung abscess, one suppurative pericarditis, and five cases of sinusitis were also due to this bacterium. In conclusion, P cepacia is responsible for excess morbidity and mortality after LTX. This organism is particularly lethal if isolated for the first time after LTX. Factors predicting its acquisition in this setting are unknown. While it is possible that the facial sinuses may act as an unrecognized reservoir or that patients or equipment provide a source, further study into the epidemiology of this organism is necessary to improve the survival of colonized patients undergoing LTX.

Study Objective To ascertain the incidence, types, morbidity, and mortality of infectious episodes in isolated lung transplant recipients. Design Retrospective chart review of patients who have undergone transplants over a six-year period in one institution. Patients Twenty-three single and 17 double lung transplants followed up between 2 and 68 months. Results Fifty-one episodes of infection occurred in the group with a slight predominance in the double lung transplants. The 32 episodes of bacterial infection constituted the largest group of infection and more than half of these were pneumonias. Organisms identified were predominantly Gram negative. While bacterial processes made up the bulk of infections, fatalities were rare. Viral and fungal infections were less common, but more often fatal. Of six cases of viral pneumonitis, two were fatal; two of five cases of invasive fungal infection were also fatal. Overall, six patients died of infection. Conclusion Our findings support previous reports from heart-lung centers documenting a high rate of infectious complications, particularly pneumonia, in recipients of lung grafts. In our experience, bacterial infections are the most common (two of three infections), but have the lowest mortality. Efforts should be directed toward establishing effective prophylaxis programs and early detection of infection.

6535 Background: NCIC CTG JBR.10 was a North American Intergroup phase III trial of adjuvant vinorelbine/cisplatin after resection of stage IB or II NSCLC, that demonstrated improved disease-free a...

7009 Background: Recent trials have shown significant survival benefit from adjuvant chemotherapy after resection of NSCLC. Whether elderly patients tolerate platinum-based adjuvant chemotherapy and derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, chemotherapy delivery and toxicity in NCIC CTG BR.10. Methods: Pretreatment characteristics and survival benefit from treatment were compared for patients ≤65 & >65. Chemotherapy delivery and toxicity were compared for 213 treated patients. Results: There were 327 young and 155 elderly patients. Baseline prognostic factors by age were similar with the exception of histology (adeno 58% young, 43% elderly; squamous 32% young, 49% elderly; p=0.001) and PS (PS 0 53% young, 41% elderly; p=0.01). Overall survival by age showed a trend favoring the young in univariate (HR 0.77, CI 0.58–1.04, p=0.084) and multivariate analyses (HR 0.75, CI 0.56–1.01, p=0.059). Patients >75 years had significantly shorter survival than those aged 66–74 (HR 1.95, CI 1.11–3.41, p=0.02). Overall survival for patients >65 was significantly better with chemotherapy v observation (HR 0.61, CI 0.38–0.98, p=0.04). Chemotherapy administration and toxicity were evaluated in 63 elderly and 150 young patients. Mean dose intensities of vinorelbine (V) and cisplatin (C) were 13.2 and 18.0 in the young and 9.9 and 14.1 in the elderly (V p=0.0004; C p=0.001). The elderly received significantly fewer doses of V (p=0.014) and C (p=0.006). Fewer elderly patients completed treatment and more refused treatment compared to the young (p=0.03). There were no significant differences in toxicities, G-CSF use or hospitalization by age group, except for myalgias and mood alteration (more frequent among the young). Six of 126 deaths (4.8%) in the young were from non-malignant causes v 12 of 71 (16.9%) in the elderly (p=0.008). Conclusions: In spite of receiving less chemotherapy than young patients, adjuvant chemotherapy improves overall survival in patients aged >65 with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients, although patients >75 years of age require further study. No significant financial relationships to disclose.

7155 Background: NCIC CTG JBR.10 is among the landmark trials to establish 3rd generation platinum-based adjuvant chemotherapy as standard of care after complete resection of stages IB-II NSCLC, improving 5-year survival by 15% and median survival by 21 months (p 0.04). The cost-effectiveness of adjuvant chemotherapy from the perspective of Canada’s public health care system was undertaken in a retrospective analysis based on the JBR.10 study population. Methods: Direct medical resource utilization data, from prospective trial data of patients enrolled onto the BR.10 trial at the 5 largest accruing Canadian centres, were identified and collected retrospectively. Direct medical costs included treatment, hospitalization and procedures. Data were captured from the time of randomization until death or study closure (April, 2004). Non-medical direct and indirect costs were not included. Available costs are presented both with and without discounting at 5% per year. Costs (2005 $CAN) were obtained from provincial sources. Average costs per treatment arm (adjuvant chemotherapy vs. observation) were calculated. Basic demographic statistics were calculated. Results: Utilization data were collected from 172 patients (36% of the trial population), 83 randomized to observation and 89 to chemotherapy. Preliminary results are available for the non-drug related costs of direct medical care including hospitalization and procedures. The mean cost of treatment for patients in the observation arm is $15,323 (25–75% IQR $1,933-$17,831), and $18,701 (25–75% IQR $2,873-$18,781) for patients in the adjuvant chemotherapy arm (2005 $CAN). Conclusion: Non-drug related costs are only slightly higher in patients treated with adjuvant chemotherapy in the NCIC BR.10 trial, despite substantially longer survival for this group of patients. These preliminary results will be updated and cost effectiveness data will be available in May 2006. No significant financial relationships to disclose.

7200 Background: Cisplatin ACT induced anemia may correlate with adverse events (AEs), poor Quality of Life (QoL), inability to deliver ACT, relapse free survival (RFS) or overall survival (OS). Me...

7018 Background: In meta-analyses platinum based adjuvant chemotherapy using 2nd generation regimens increased cure rate by 5% in completely resected NSCLC. JBR.10 was undertaken to determine wheth...

Background The efficacy of prophylaxis against stress ulcers in preventing gastrointestinal bleeding in critically ill patients has led to its widespread use. The side effects and cost of prophylaxis, however, necessitate targeting preventive therapy to those patients most likely to benefit. Methods We conducted a prospective multicenter cohort study in which we evaluated potential risk factors for stress ulceration in patients admitted to intensive care units and documented the occurrence of clinically important gastrointestinal bleeding (defined as overt bleeding in association with hemodynamic compromise or the need for blood transfusion). Results Of 2252 patients, 33 (1.5 percent; 95 percent confidence interval, 1.0 to 2.1 percent) had clinically important bleeding. Two strong independent risk factors for bleeding were identified: respiratory failure (odds ratio, 15.6) and coagulopathy (odds ratio, 4.3). Of 847 patients who had one or both of these risk factors, 31 (3.7 percent; 95 percent confidence ...

Pleural complications occurred in 30 (22%) of 138 patients after 53 single and 91 double lung transplants between September 1986 and February 1993. These were defined for the purpose of this study as pneumothorax persisting beyond the first 14 postoperative days, recurrent pneumothorax, or any other pleural process that necessitated diagnostic or therapeutic intervention. Overall, a higher pleural complication rate was seen in double lung transplantation (25 of 30) than in single lung transplantation (5 of 30) with no differences noted in the frequency among preoperative diagnostic groups (p > 0.05). Pneumothorax was the most frequent complication, affecting 14 of 30 patients, with 6 of 14 cases occurring after transbronchial biopsy. All pneumothoraces in single (n = 4) and double lung transplantation (n = 10) resolved spontaneously or with chest tube thoracostomy. One patient required placement of a Clagett window after open lung biopsy and another required thoracotomy and pleural abrasion after transbronchial biopsy. Parapneumonic effusion was observed in 4 of 30 double lung transplantations with spontaneous resolution in all cases. Empyema affected 7 of 30 patients and occurred exclusively in the double lung transplant group. Sepsis developed in three of the patients with this complication and they subsequently died. The risk of empyema was independent of preoperative diagnosis (p > 0.05). Of interest, all patients with cystic fibrosis (n = 3) with complicating empyema had Pseudomonas cepacia in the pleural fluid. Other miscellaneous complications included subpleural hematoma, chylothorax, and hemothorax. The latter two necessitated thoracic duct and bronchial artery ligation, respectively. In summary, a significant proportion of lung transplant recipients will have pleural space complications. The vast majority of these will resolve spontaneously or with conservative procedures. These complications were not related to preoperative diagnosis nor associated with a significant prolongation of hospital stay (p > 0.05). Empyema is the only pleural space complication associated with increased patient mortality and, as such, is an important clinical marker for those at risk for sepsis and death.