Role of surgical resection in colorectal lung metastases: analysis of 137 patients.

PURPOSE: The aim of this study is to investigate clinicopathologic characteristics and to identify prognostic factors in patients undergoing pulmonary metastasectomy for colorectal carcinoma. METHODS: This study is a single-institution retrospective study of 137 consecutive patients who underwent 158 pulmonary resections for metastatic colorectal carcinoma between January 1989 and June 2008. RESULTS: Median disease-free interval between colorectal resection and pulmonary metastasectomy was 35.6 months (range, 0.6 to 154.3 months). No perioperative deaths occurred. Follow-up was 100% complete and mean follow-up was 41.6 ± 27.6 months. Median survival was 36.2 months (range, 4.6 to 126 months). Overall 5- and 10-year survival rates were 55.4% and 30.8%, respectively, after pulmonary metastasectomy. At univariate analysis of patient survival, number of lung metastases (p = 0.002), disease-free interval of more than 24 month (p = 0.013), and absence of residual tumor (p = 0.024) were significant prognostic factors. At multivariate analysis, presence of solitary lung metastasis and disease-free interval of more than 24 months remained significant prognostic factors. There was no significant difference in the 5-year survival for 121 patients undergoing single thoracotomy compared with 16 patients undergoing repeated resection(s) for recurrent colorectal lung metastasis (55.1% vs 59.5%; p = 0.79). Nor was the presence of hepatic metastasis associated with lower outcome (p = 0.77). CONCLUSIONS: Disease-free interval and number of metastases are the most significant prognostic factors for survival after pulmonary metastasectomy for colorectal carcinoma. Recurrent pulmonary disease can benefit from repeated resection. Prior hepatectomy for liver involvement does not influence survival.

Malignant pleural mesothelioma: clinicopathologic and survival characteristics in a consecutive series of 394 patients.

OBJECTIVE: Treatment of malignant pleural mesothelioma (MPM) remains disappointing, although recent reports suggest that multimodality therapy including surgery may provide a significant survival benefit. The aims of this single institution study were: to investigate clinicopathologic characteristics and potential prognostic factors in MPM patients, and to ascertain whether surgery followed by adjuvant therapy had an independent prognostic role. METHODS: Retrospective review of a prospectively compiled computerized database of all patients with MPM evaluated between 1989 and 2003. Kaplan-Meier method, log-rank test, and Cox model were used in the statistical analysis. RESULTS: There were 394 patients: 270 men (68.5%), 124 women, median age 64 (range 28-93). Twenty-seven patients (6.8%) underwent surgical resection (extrapleural pneumonectomy 15, pleurectomy/decortication 12), followed by adjuvant therapy. As of March 2006, 381 patients (96.7%) had died (median survival, 11.7 months; range 0.03-117.9). Median follow-up of 13 surviving patients (3.3%) was 45.2 months (range 28.7-126.5). Overall survival at 2 years was 18.8%. Multimodality therapy including surgery yielded a median survival of 14.5 months and a 2-year survival rate of 29.6%. Using univariate analysis, age (p=0.009), chest pain (p=0.01), weight loss (p=0.001), performance status (p=0.0001), platelet count (p=0.008), histology (p=0.0001), macroscopic appearance of pleural surface (non-specific inflammation, tumor-like thickening, or nodules; p=0.0001), visceral pleura involvement (p=0.0001), degree of involvement of pleural cavity (less than or more than one third of the cavity; p=0.0001), and multimodality therapy (p<0.01) were found to be significant prognostic factors. At multivariate analysis, performance status, platelet count, histology, and degree of involvement of pleural cavity remained independently associated with survival, whereas multimodality therapy failed to enter the model. CONCLUSIONS: Significant predictors of survival include performance status, platelet count, histology, and degree of involvement of pleural cavity. Within the confines of this retrospective study and the small number of patients undergoing multimodality therapy, the role of surgery in the treatment of MPM remains unclear. Further investigation is warranted to determine the optimal treatment strategy in this disease.

Lung cancer stage is an independent risk factor for surgical mortality.

AIMS AND BACKGROUND: To study surgical mortality and evaluate major risk factors, with specific focus on the role of pathological stage in patients undergoing lung cancer resection. METHODS AND STUDY DESIGN: Age, gender, comorbidity, resection volume, experience of the hospital and surgical team have been reported as variables related to postoperative morbidity and mortality in lung cancer. The role of pathological tumor stage on postoperative mortality has never been fully evaluated. The study included 1418 consecutive lung cancer resections performed from 1998 to 2002 in two institutions. The effect of age, gender, comorbidity, resection volume, pathological stage and induction therapies on postoperative mortality was assessed by univariable and multivariable logistic regression analysis. RESULTS: Postoperative mortality was 1.8% overall, 3.7% (9/243) for pneumonectomy, 1.7% (17/1016) for lobectomy, and null (0/159) for sublobar resections (P = 0.020). At multivariable analysis, cardiovascular comorbidity (P = 0.008), resection volume (P = 0.036) and pathological stage (P = 0.027) emerged as significant predictors of surgical mortality. CONCLUSIONS: Early stage lung cancer resection has a favorable effect on surgical mortality, not only by preventing the need for pneumonectomy, but also by reducing mortality after lobectomy.

Prognostic role of protease-activated receptors 1 and 4 in resected stage IB non-small-cell lung cancer.

BACKGROUND: Protease-activated receptor (PAR)-1 and PAR-4 are involved in extracellular matrix invasion and angiogenesis. PATIENTS AND METHODS: A series of 60 resected stage IB non-small-cell lung cancers (NSCLCs), including 30 adenocarcinomas (ADCs) and 30 squamous cell carcinomas (SCCs), were processed by immunohistochemistry with antibodies to PAR-1, PAR-4, vascular endothelial growth factor (VEGF), and CD34. RESULTS: Protease-activated receptor-1 was expressed in 37 cases (62%) and PAR-4 in 39 (65%). Adenocarcinomas were significantly more positive than SCC for PAR-1 (17 vs. 8 cases) and PAR-4 (10 vs. 5 cases). Vascular endothelial growth factor was expressed in 42 cases (70%): 22 ADC and 20 SCC. A significant correlation emerged between PAR-1 and/or PAR-4 expression and VEGF but not with microvessel density. Median follow-up was 38 months; actuarial 5-year survival was 43%. At univariate analysis, 3-year survival was shorter in patients expressing PAR-4 versus negative cases (29% vs. 60%; P = 0.002). In 46 patients expressing PAR-1 and/or PAR-4, 3-year survival was 30% versus 68% in 14 patients with no PAR expression (P = 0.002). A trend toward shorter 3-year survival was seen in PAR-1-positive versus PAR-1-negative cases (34% vs. 46%; P = 0.06). Multivariate analysis identified expression of PAR-1 and/or PAR-4 as an independent prognostic factor for reduced survival in resected stage IB NSCLC. CONCLUSION: Expression of PAR-1 and PAR-4 in early-stage NSCLC could be included in a molecular algorithm for the selection of patients eligible for adjuvant studies.

A suitable system of reconstruction with titanium rib prosthesis after chest wall resection for Ewing sarcoma.

The recent improvements in chemotherapy and surgical resection in Ewing sarcoma (ES) increased the overall survival as well as the importance of chest wall reconstruction. These improvements are in order to avoid asymmetrical growth, functional and cosmetic compromise after surgery. Chest wall reconstruction still remains a big issue in young patients with ES. We present a case of ES of the left chest wall, arising from a rib, in a 14-year-old patient. He was admitted after neoadjuvant chemotherapy and radiotherapy. The patient underwent a chest wall resection of three ribs and a wedge lung resection of the upper lobe followed by chest wall reconstruction with Stratos™ rib titanium prostheses. This new device is suitable for reconstruction after major chest wall resection with good cosmetic and functional results. During the follow-up, there was no evidence of local and distant recurrence, the pain was under control and there were no functional alterations in the chest wall.

Suitable device for thoracoscopic talc poudrage in malignant pleural effusion.

Chemical pleurodesis is widely used in symptomatic patients with malignant pleural effusion to relieve symptoms, prevent fluid recurrence, and improve quality of life. Talc has been repeatedly found to be the most effective sclerosant agent, and thoracoscopic talc poudrage has been found to be the most effective pleurodesis technique. A homogeneous talc distribution on the visceral and parietal pleura helps to achieve complete pleural symphysis. We have recently adopted a new suitable sterile device that delivers talc under low and constant pressure, facilitating uniform coating of the whole pleural surface and avoiding inappropriate deposition of talc clumps.

Air leaks following pulmonary resection for malignancy: risk factors, qualitative and quantitative analysis.

Air leaks are a common complication of pulmonary resection. The aims of this study were to analyze risk factors for postoperative air leak and to evaluate the role of air leak measurement in identifying patients at increased risk for cardiorespiratory morbidity and prolonged air leak. From March to December 2009, 142 consecutive patients underwent pulmonary resection for malignancy and were prospectively followed up. Preoperative and intraoperative risk factors for air leak were evaluated. Air leaks were qualitatively and quantitatively labeled twice daily. There were 52 (36.6%) patients who had an air leak on day 1, and 32 (22.5%) who had an air leak on day 2. Air leak was ≥180 ml/min in 12 (37.5%) of these patients. Independent predictors of air leak on day 2 included type of pulmonary resection, presence of adhesions, and incomplete fissures. Cardiorespiratory morbidity was significantly higher (34.4%) in patients who experienced air leak on day 2 than in those who did not (10.9%) (P=0.002). Nine (75%) out of 12 patients with air leak ≥180 ml/min on day 2 had prolonged air leak (greater than five days) (P=0.0001).

Stereotactic body radiation therapy for early stage non-small cell lung cancer: results of a prospective trial.

Patients affected with early stage (IA-IB) non-small cell lung cancer (NSCLC), deemed medically inoperable, are usually treated by conventional 3D-CRT, with poor results in terms of local tumour control and survival. Hypofractionated stereotactic body radiation therapy (SBRT) appears to be a valid alternative option, with high rates of local control and promising survival rates according to recent reported series. We herein report the final results of a prospective phase II trial of SBRT in 62 stage I NSCLC patients, homogeneously treated with three fractions of 15Gy each, given every other day during a 1 week time, up to a total dose of 45Gy; dose was prescribed to the 80%-isodose encompassing planning target volume. Patients were immobilized in a dedicated stereotactic body frame; margins around gross tumour volume were 5mm in the axial plane and 10mm in the longitudinal direction. Median age was 73.7 years. A pathologic confirmation of NSCLC was obtained in 64.5% of patients. Forty-three patients had stage IA and 19 stage IB disease. The majority of patients did not experience any toxicity; mild skin reactions, fatigue, dyspnea/cough or transient thoracic pain were recorded in approximately 10% of patients. With a median follow-up time of 28 months, 2 patients experienced an isolated local relapse, 4 an isolated nodal relapse and 15 a systemic failure. At 3 years, local control rate was 87.8%, cancer-specific survival 72.5%, overall survival 57.1%, with 8 out of 20 non-cancer related deaths. In multivariate analysis, tumour volume was associated with a better outcome. In our series, SBRT was well tolerated and confirmed its efficacy, with local control and survival rates globally superior to those reported using conventional radiotherapy. A longer follow-up is needed in order to establish a correct comparison with surgical series, and to fully ascertain a potential negative impact of SBRT on comorbidities of such a fragile patients population.

Preoperative intrathoracic lymph node staging in patients with non-small-cell lung cancer: accuracy of integrated positron emission tomography and computed tomography.

OBJECTIVE: To evaluate the accuracy of integrated positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (FDG) and computed tomography (PET/CT) in preoperative intrathoracic lymph node staging in patients with non-small-cell lung cancer (NSCLC) and to ascertain the role of invasive staging in verifying positron emission tomography (PET)/computed tomography (CT) results. METHODS: Retrospective, single institution study of consecutive patients with suspected or pathologically proven, potentially resectable NSCLC undergoing integrated PET/CT scanning in the same PET centre. Lymph node staging was pathologically confirmed on tissue specimens obtained at mediastinoscopy and/or thoracotomy. Statistical evaluation of PET/CT results was performed on a per-patient and per-nodal-station bases. RESULTS: A total of 1001 nodal stations (723 mediastinal, 148 hilar and 130 intrapulmonary) were evaluated in 159 patients. Nodes were positive for malignancy in 48 (30.2%) out of 159 patients (N1=17; N2=30; N3=1) and 71 (7.1%) out of 1001 nodal stations (N1=24; N2=46; N3=1). At univariate analysis, lymph node involvement was significantly associated (p<0.05) with the following primary tumour characteristics: increasing diameter, maximum standardised uptake value >9, central location and presence of vascular invasion. PET/CT staged the disease correctly in 128 out of 159 patients (80.5%), overstaging occurred in nine patients (5.7%) and understaging in 22 patients (13.8%). The overall sensitivity, specificity, positive and negative predictive values, and accuracy of PET/CT for detecting metastatic lymph nodes were 54.2%, 91.9%, 74.3%, 82.3% and 80.5% on a per-patient basis, and 57.7%, 98.5%, 74.5%, 96.8% and 95.6% on per-nodal-station basis. With regard to N2/N3 disease, PET/CT accuracy was 84.9% and 95.3% on a per-patient basis and on per-nodal-station basis, respectively. Referring to nodal size, PET/CT sensitivity to detect malignant involvement was 32.4% (12/37) in nodes <10mm, and 85.3% (29/34) in nodes > or = 10mm. CONCLUSION: Our data show that integrated PET/CT provides high specificity but low sensitivity and accuracy in intrathoracic nodal staging of NSCLC patients and underscore the continued need for surgical staging.

Non-small cell lung cancer exhibits transcript overexpression of genes associated with homologous recombination and DNA replication pathways.

Genes involved in DNA repair and replication have been recently investigated as predictive markers of response to chemotherapy in non-small cell lung cancer (NSCLC). However, few data on the expression of these genes in tumor compared with corresponding normal lung are available. The aim of this study was to evaluate differential mRNA levels of 22 DNA repair genes of five different DNA repair pathways: direct, base excision, nucleotide excision (NER), double-strand break (DSBR), and postreplicative repair. In addition, six genes involved in DNA replication (REP) and three telomere maintenance genes were investigated. Total RNAs extracted from fresh-frozen tumors and corresponding normal tissues of 50 consecutive chemo-naïve resected NSCLC patients were analyzed. Transcript levels were quantified by real-time PCR. A significant overexpression was detected in 20 of 30 (67%) genes, mostly belonging to DSBR pathways, whereas others (XPA, XPC, and UBE2N; 10%) were significantly underexpressed. For 7 of 30 (23%) genes, mostly belonging to NER pathway, no significant difference between paired tumor and normal samples was observed. Transcript overexpression of DSBR and REP genes was significantly higher in poorly differentiated carcinomas and DSBR levels were higher in men compared with women. The transcriptional overexpression of four genes (XRCC5, TOP3B, TYMS, and UNG) showed significant correlation with a shorter patients' outcome at the univariate, whereas only stage of disease appeared as an independent factor affecting prognosis, as assessed by multivariate analysis. In conclusion, genes belonging to DNA repair/replication pathways are overexpressed in NSCLC and are associated with a more aggressive phenotype.

Epidermal growth factor ligand/receptor loop and downstream signaling activation pattern in completely resected nonsmall cell lung cancer.

BACKGROUND: In recent years, molecular insights shed light on the role of the epidermal growth factor receptor (EGFR) in nonsmall cell lung cancer (NSCLC), and new therapeutic agents, such as the EGFR tyrosine kinase inhibitors, were tested successfully, with responsiveness to those agents more likely in those patients with specific EGFR gene alterations. The objective of the current study was to investigate the protein profiles of EGFR, c-erb-B2, transforming growth factor alpha (TGF-alpha) (one of the EGFR ligands commonly expressed in NSCLC), and some downstream molecules, potentially to detect a subset of tumors with an activated autocrine loop that is responsible for higher intracellular signaling. METHODS: One hundred twelve consecutive patients with resected NSCLC were analyzed by immunohistochemistry for EGFR, the c-erb-B2 receptor, TGF-alpha, and pivotal molecules downstream from EGFR activation. Statistical correlations between the investigated molecular expression profiles and clinicopathologic data were performed. RESULTS: EGFR, c-erb-B2, TGF-alpha and downstream molecule expression, per se, was not correlated significantly with any clinicopathologic variables, with the exception of a significant correlation between squamous histology and EGFR and between adenocarcinoma and TGF-alpha. However, nearly 30% of NSCLCs demonstrated coexpression of both TGF-alpha and EGFR, and this molecular status was associated positively with a statistically significant expression of phosphatidylinositol 3 kinase and an inversely with mitogen-activated protein kinase expression. CONCLUSIONS: The presence of a subgroup of NSCLCs with an activated autocrine loop may help to explain the mechanisms that lead to the relative ineffectiveness of the EGFR tyrosine kinase inhibitor and may support new clinical trials to define whether the subgroup of patients with these tumors reasonably may benefit from higher doses of such inhibitors or from the simultaneous inhibition of EGFR downstream signaling targets.

Bone sialoprotein is predictive of bone metastases in resectable non-small-cell lung cancer: a retrospective case-control study.

PURPOSE: Bone metastases (BM) in non-small-cell lung cancer (NSCLC) may be detected at diagnosis or during the course of the disease, and are associated with a worse prognosis. Currently, there are no predictive or diagnostic markers to identify high-risk patients for metastatic bone dissemination. PATIENTS AND METHODS: Thirty patients with resected NSCLC who subsequently developed BM were matched for clinicopathologic parameters to 30 control patients with resected NSCLC without any metastases and 26 patients with resected NSCLC and non-BM lesions. Primary tumors were investigated by immunohistochemistry for 10 markers involved in bone resorption or development of metastases. Differences among groups were estimated by chi2 test, whereas the prognostic impact of clinicopathologic parameters and marker expression was evaluated by univariate (Wilcoxon and Mantel-Cox tests) and multivariate (Cox proportional hazards regression model) analyses. RESULTS: The presence of bone sialoprotein (BSP) was strongly associated with bone dissemination (P < .001) and, independently, with worse outcome (P = .02, Mantel-Cox test), as defined by overall survival. To evaluate BSP protein expression in nonselected NSCLC, a series of 120 consecutive resected lung carcinomas was added to the study, and BSP prevalence reached 40%. No other markers showed a statistically significant difference among the three groups or demonstrated a prognostic impact, in terms of both overall survival and time interval to metastases. CONCLUSION: BSP protein expression in the primary resected NSCLC is strongly associated with BM progression and could be useful in identifying high-risk patients who could benefit from novel modalities of surveillance and preventive treatment.

Low dose CT in early lung cancer diagnosis: Prevalence data.

PURPOSE: Lung cancer has a high mortality rate and its prognosis largely depends on early detection. We report the prevalence data of the study on early detection of lung cancer with low-dose spiral CT underway at our hospital. MATERIALS AND METHODS: Since the beginning of 2001, 519 asymptomatic volunteers have undergone annual blood tests, sputum tests, urinalyses and low-dose spiral CT. The inclusion criteria were age (=/> 55 years old), a history of cigarette smoking and a negative history for previous neoplastic disease. The diagnostic workup varied depending on the size and CT features of the nodules detected. RESULTS: At baseline, the CT scan detected nodules > 5 mm in 22% of subjects; the nodules were single in 42 and multiple in 71. In 53% of cases the findings were completely negative, while in 122 (23.4%) nodules with a diameter < 5 mm were detected. Six cases of lung cancer were identified, of which four were stage I, one stage was IIIB and one was stage IV with adrenal metastases. CONCLUSIONS: Our preliminary data on spiral CT as a potential new diagnostic tool for lung cancer screening, although less promising than the Japanese and ELCAP results, confirm the feasibility of the technique. Additional validation is, however, required.

Independent high-frequency oscillatory ventilation in the management of asymmetric acute lung injury.

We present a case of independent lung ventilation in an adult with asymmetric acute lung injury. We applied a conventional protective ventilatory strategy to the more homogeneously infiltrated lung and high-frequency oscillatory ventilation to the almost totally collapsed lung, because a conventional protective strategy exposed this lung to plateau pressure more than 30 cm H2O, whereas high-frequency oscillatory ventilation provided sufficient gas exchange at safer pressure levels. Analysis of a lung computed tomography scan was used to evaluate the efficacy of the ventilatory strategy.

HER-2/neu overexpression in patients with radically resected nonsmall cell lung carcinoma. Impact on long-term survival.

BACKGROUND: Using immunohistochemistry, the authors prospectively investigated the expression of HER-2/neu protein in radically resected specimens of nonsmall cell lung carcinoma (NSCLC) and evaluated its impact on long-term prognosis. METHODS: Between January 1991 and February 1992, surgical specimens from 130 consecutive patients who underwent radical resection for NSCLC (60 squamous cell carcinoma, 48 adenocarcinoma cases, and 22 large cell carcinomas) and that were staged (according to the TNM staging system) pathologically as Stage I (41 cases [32%]), Stage II (37 cases [28%]), and Stage IIIA (52 cases [40%]) were investigated for the expression of HER-2/neu using an avidin-biotin complex immunohistochemical technique. A semiquantitative four-stage grading system was used (0%, 1-5%, 6-20%, and > 20% positive cells) and an average number of 1500 cells/section was considered. Data were correlated with clinical and pathologic variables. RESULTS: Normal bronchial tissue was found to be completely negative for HER-2/neu expression whereas 21 of the 130 tumor specimens (16%) were positive (range 1-> 20%). HER-2/neu positivity did not appear to differ significantly among pathologic stages and histotypes. Using a predetermined cutoff value of 5% positive cells, 15 tumor specimens (12%) were found to be above this value. The median survival time (85 weeks vs. 179 weeks) and overall survival rate were significantly lower in patients with > 5% HER-2/neu-positive tumors (hazard ratio for the group with > 5% positive cells: 2.94, 95% confidence interval, 1.62-5.34; P < 0.0004). On multivariate analysis, HER-2/neu and extent of tumor emerged as independent factors for disease-related mortality. CONCLUSIONS: In NSCLC, the negative impact of HER-2/neu overexpression on survival was maintained in the long-term follow-up of radically resected patients. HER-2/neu overexpression may be a valuable prognostic factor as well as a potential target for biologic therapies.