MicroRNA and mRNA features of malignant pleural mesothelioma and benign asbestos-related pleural effusion.

INTRODUCTION: We investigated the expression of microRNAs and mRNAs in pleural tissues from patients with either malignant pleural mesothelioma or benign asbestos-related pleural effusion. METHODS: Fresh frozen tissues from a total of 18 malignant pleural mesothelioma and 6 benign asbestos-related pleural effusion patients were studied. Expression profiling of mRNA and microRNA was performed using standard protocols. RESULTS: We discovered significant upregulation of multiple microRNAs in malignant pleural mesothelioma compared to benign asbestos-related pleural effusion. Hsa-miR-484, hsa-miR-320, hsa-let-7a, and hsa-miR-125a-5p were able to discriminate malignant from benign disease. Dynamically regulated mRNAs were also identified. MET was the most highly overexpressed gene in malignant pleural mesothelioma compared to benign asbestos-related pleural effusion. Integrated analyses examining microRNA-mRNA interactions suggested multiple altered targets within the Notch signaling pathway. CONCLUSIONS: Specific microRNAs and mRNAs may have diagnostic utility in differentiating patients with malignant pleural mesothelioma from benign asbestos-related pleural effusion. These studies may be particularly helpful in patients who reside in a region with a high incidence of mesothelioma.

Generation and sequencing of pulmonary carcinoid tumor cell lines.

INTRODUCTION: Pulmonary carcinoid tumors account for approximately 5% of all lung malignancies in adults, and comprise 30% of all carcinoid tumors. There are limited reagents available to study these rare tumors, and consequently no major advances have been made for patient treatment. We report the generation and characterization of human pulmonary carcinoid tumor cell lines to study underlying biology, and to provide models for testing novel chemotherapeutic agents. METHODS: Tissue was harvested from three patients with primary pulmonary typical carcinoid tumors undergoing surgical resection. The tumor was dissociated and plated onto dishes in culture media. The established cell lines were characterized by immunohistochemistry, Western blotting, and cell proliferation assays. Tumorigenicity was confirmed by soft agar growth and the ability to form tumors in a mouse xenograft model. Exome and RNA sequencing of patient tumor samples and cell lines was performed using standard protocols. RESULTS: Three typical carcinoid tumor lines grew as adherent monolayers in vitro, expressed neuroendocrine markers consistent with the primary tumor, and formed colonies in soft agar. A single cell line produced lung tumors in nude mice after intravenous injection. Exome and RNA sequencing of this cell line showed lineage relationship with the primary tumor, and demonstrated mutations in a number of genes related to neuronal differentiation. CONCLUSION: Three human pulmonary typical carcinoid tumor cell lines have been generated and characterized as a tool for studying the biology and novel treatment approaches for these rare tumors.

Surgical management of lung cancer.

Lung cancer continues to be the most frequent cancer-related cause of death in the United States and throughout the world. Surgical resection is currently the most effective treatment in early-stage non-small-cell lung cancer, and historically the only treatment approach achieving significant cure rates. In advanced disease, therapeutic approaches involving chemotherapy and/or radiation therapy are utilized to improve prognosis, either as part of a neoadjuvant treatment approach followed by surgical resection or as definitive treatment alone. The role of surgery in locally advanced or metastatic non-small-cell lung cancer remains controversial, with more studies required to further refine the application of modern surgical techniques. For any treatment approach, thorough preoperative staging as well as careful patient selection are essential to assess the benefits and risks involved for the patient. Surgical management of early-stage non-small-cell lung cancer and its role in more advanced disease are discussed in this review.

Bronchial resection margin length and clinical outcome in non-small cell lung cancer.

OBJECTIVE: Complete surgical resection with pathologic negative margin is associated with the best prognosis in early-stage non-small-cell lung cancer (NSCLC). However, the impact of the length of the bronchial margin remains unknown. This study aimed to determine whether an increased bronchial resection margin length is correlated with an improved disease-free and overall survival rate. METHODS: A total of 3936 consecutive pulmonary resections were performed between 25 June 1992 and 31 December 2007 at Mayo Clinic Rochester. A subset consisting of 496 patients with completely resected lesions (R0-resection), and a documented bronchial margin length was analyzed retrospectively. RESULTS: There were 340 men (68.5%) and 156 women (31.5%), with a mean age of 65.9±10.6 years. All patients underwent anatomic lobectomy or larger resection. Final pathology confirmed complete resection without microscopic residual tumor (R0-resection) in all patients. Mean length of the bronchial resection margin was 23.3±15.9mm. Overall, 190 patients (38.3%) suffered from disease recurrence with local recurrence in 35 patients, distant recurrence in 101, and both local and distant recurrence in 54 patients. Overall 5-year and 10-year local recurrence-free survival was 72.5% (95% confidence interval (CI): 67.3-78.1) and 68.0% (95% CI: 62.1-74.4), distant recurrence free survival 61.0% (95% CI: 55.8-66.6) and 52.9% (95% CI: 46.7-60.1) and overall survival 50.0% (95% CI: 45.1-55.3) and 28.8% (95% CI: 23.8-34.7). Tumor size and N-stage were associated with a worse prognosis in terms of local and distant recurrence, as well as survival (p<0.05). Histology was not significantly associated with local recurrence (p=0.28), though adenocarcinoma relative to squamous cell carcinoma was associated with an increased risk of distant recurrence (p<0.01). There was no significant association between type of surgical resection and local (p=0.37) or distant recurrence (p=0.37). Neither local (p=0.56) or distant recurrence (p=0.46), nor survival (p=0.54) was associated with the bronchial margin length. In multivariate models including age, N-stage, and gender there were no significant overall associations of margin length (≤5, 6-10, 11-15, 16-20, >20mm) and local recurrence (p=0.51), distant recurrence (p=0.33), or survival (p=0.75). CONCLUSIONS: When complete surgical resection is achieved, the extent of the bronchial margin has no clinically relevant impact on disease-free and overall survival in NSCLC.

Pretreatment assessment for the optimal management of early-stage lung cancer.

Optimal management of non-small cell lung cancer requires treatment approach to be tailored to both the particular disease stage and the overall health and functional status of the patient. Even though surgical resection by means of an anatomic lobectomy remains the treatment of choice with the goal of cure for early-stage lung cancer, it is an invasive procedure with associated morbidity and mortality. Although these risks continue to decrease in the modern era with improvements in surgical technique and perioperative management, the risks are elevated in patients with associated medical comorbidities. As a consequence, patients at potentially increased or high risk for surgical lobectomy need to be identified by a structured preoperative assessment. This has gained increasing importance, given the emergence of alternative treatment approaches such as minimally invasive surgery, less extensive pulmonary resection, and stereotactic body radiation therapy. We review the clinical approach to suspected early-stage lung cancer based on a tumor and patient-centered stratification of risk and benefit.

Outcome of lung transplantation in elderly recipients.

OBJECTIVE: Lung transplantation is a standard treatment option for patients with end-stage lung disease. Lung transplantation in the elderly is controversial due to concerns over anticipated increased surgical risks, inferior long-term outcomes and proper stewardship in allocating limited donor organs. With demographic trends showing an increasing proportion of patients over 60 years old, we evaluated our outcomes with lung transplantation in this older cohort. METHODS: Between January 1990 and July 2009, 142 patients underwent lung transplantation at our institution. A total of 15 patients receiving heart/lung transplantation and one patient declining research participation were excluded. As many as 126 patients were analyzed in two groups: <60 and ≥ 60 years old. RESULTS: There were 65 females (52%) and 61 males (48%). A total of 53 patients (42%) underwent bilateral sequential lung transplantation and 73 patients single-lung transplantation (58%). Median age at transplantation was 55.3 years (range, 21.6-73.1 years) with 94 patients <60 years (75%) and 32 patients ≥ 60 years (25%). Median follow-up was 4.3 years (range, 0-17.8 years). Overall survival at 30 days was 93.7% with no difference between age groups (p=0.95). There was no difference between the groups for in-hospital, postoperative complications (p=0.86), or unplanned readmission rates within 90 days of the hospitalization (p=0.26). Postoperative pulmonary function (forced expiratory volume in 1s (FEV1) % predicted) at transplant, 4 weeks, 3 months, and 6 months after transplantation was not different between groups (p=0.93). No difference in long-term survival was observed (p=0.59), with 5-year survival of 52.2% for patients <60 years and 47.3% for patients ≥ 60 years. Overall, 20 patients developed bronchiolitis obliterans syndrome and 13 posttransplant lymphoproliferative disease, which was not statistically different between age groups (p=0.87, p=0.37, respectively). CONCLUSION: Increased age of 60 years and greater, in highly selected patients, does not appear to have a significant impact on the short- or long-term outcome in patients undergoing lung transplantation. Judicious selection of older patients, who are otherwise excellent candidates for lung transplantation, remains a reasonable option.

Early experience with robotic-assisted lung resection.

OBJECTIVE: Robotic-assisted surgery is not widely accepted for general thoracic surgical procedures, and the technical advantages, cost effectiveness, and patient benefit are in question. Few reports have been published to date regarding clinical experience with this technology. We describe our first consecutive case experience with robotic-assisted lung resection. METHODS: A total of 23 robotic-assisted lung resections were performed from December 1, 2008, to September 30, 2010. Patients were selected on the basis of being candidates for a minimally invasive approach to their lung resection, including criteria such as known or suspected early-stage nonsmall-cell lung cancer, no prior thoracotomy, no neoadjuvant therapy, and a body mass index (BMI) less than 40 kg/cm². Data on patient characteristics and perioperative results were collected retrospectively. RESULTS: Overall 90-day mortality was 0%. The total postoperative complication rate was 39%. Conversion of the robotic-assisted procedure to a video-assisted procedure was necessary in four patients (17%), and to a thoracotomy in one patient (4%). We assessed operative time, chest tube duration, and length of hospital stay. Comparison to published outcomes from the Society of Thoracic Surgeons database demonstrated comparable outcomes to standard approaches. CONCLUSIONS: Robotic-assisted lung resection is safe and feasible, with comparable short-term outcomes to published results from video-assisted or open approaches.

Prospects for molecular staging of non-small-cell lung cancer from genomic alterations.

Genomic technology continues to advance, and data derived from non-small-cell lung cancer (NSCLC) tumor specimens in conjunction with clinical information are accumulating at an exponential rate. Application of this information to clinical practice for the treatment of patients with NSCLC lags behind the promise of individualized patient management based on genomic medicine. Testing treatment decisions based on genomic information in cancer clinical trials is only now being addressed. How best to incorporate the myriad of potentially available molecular diagnostics into treatment algorithms is not yet clear. Many hurdles and much work remain for the development of true, individualized treatment strategies for NSCLC based on molecular staging. Here we review some of the successes, frustrations and obstacles that exist to further progress in the field.

An alternative postoperative pathway reduces length of hospitalisation following oesophagectomy.

OBJECTIVE: As part of our ongoing quality improvement effort, we evaluated our conventional approach to post-oesophagectomy management by comparing it to an alternative postoperative management pathway. METHODS: Medical records from 386 consecutive patients undergoing oesophagectomy with gastric conduit for oesophageal cancer or Barrett's oesophagus with high-grade dysplasia were analysed retrospectively (July 2004 to August 2008). The conventional pathway involved a routine radiographic contrast swallow study at 5-7 days after oesophagectomy with initiation of oral intake if no leak was detected. In the alternative pathway, a feeding jejunostomy was placed for enteral feeding and used exclusively until oral intake was gradually initiated at home at 4 weeks after oesophagectomy. No contrast swallow was obtained in the alternative pathway group unless indicated by clinical suspicion of an anastomotic leak. Each group was analysed on an intention-to-treat basis with respect to anastomotic leak rates, length of hospitalisation, re-admission and other complications. RESULTS: A total of 276 (72%) patients underwent conventional postoperative management, 110 (28%) followed the alternative pathway. Patient characteristics were similar in both the groups. The anastomotic leak rate was lower in the alternative pathway with three clinically significant leaks (2.7%) versus 33 in the conventional pathway (12.0%; p=0.01). Among patients undergoing a radiographic contrast swallow examination, a false-negative rate of 5.8% was observed. The swallow study of 14 patients (5.9%) was complicated by aspiration of oral contrast. Postoperatively, 7.3% of patients suffered from pneumonia. There were no significant differences overall in postoperative pulmonary or cardiac complications associated with either pathway. Median length of hospitalisation was 2 days shorter for the alternative pathway (7 days) than the conventional pathway (9 days; p<0.001). There was no significant difference in unplanned re-admission rates. CONCLUSION: An alternative postoperative pathway following oesophagectomy involving delayed oral intake and avoidance of a routine contrast swallow study is associated with a shortened length of hospitalisation without a higher risk of complication after hospital discharge.

Clinical outcomes of video-assisted thoracoscopic lobectomy.

OBJECTIVE: To review our experience with video-assisted thoracoscopic (VATS) lobectomy with respect to morbidity, mortality, and short-term outcome. PATIENTS AND METHODS: VATS lobectomies were performed in 56 patients between July 6, 2006, and February 26, 2008. Two patients declined consent for research participation and were excluded. Clinical data for 54 patients were collected from medical records and analyzed retrospectively. RESULTS: The studied cohort included 19 men (35%) and 35 women (65%) with a median age of 67.5 years (minimum-maximum, 21-87 years; interquartile range [IQR], 59-74 years). Median duration of operation for VATS lobectomy was 139 minutes (minimum-maximum, 78-275 minutes; IQR, 121-182 minutes). Two cases (4%) required conversion to open lobectomy. Median time to chest tube removal was 2 days (minimum-maximum, 1-12 days; IQR, 1.3-3.8 days). Median length of stay was 4 days (minimum-maximum, 1-12 days; IQR, 4-7 days). There was no operative mortality. CONCLUSION: VATS lobectomy is safe and feasible for pulmonary resection. This minimally invasive approach may allow patients to benefit from lobectomy with shorter recovery times and hospital stays compared with conventional open thoracotomy.