Prediction of distant recurrence in resected stage I and II lung adenocarcinoma.

OBJECTIVES: Optimal procedures for adjuvant treatment and post-surgical surveillance of resected non-small-cell lung cancer remain under discussion. Pathological features are the main determinant of follow-up therapy but have limited ability to identify patients at risk of recurrence. Increasingly, molecular markers are incorporated into clinical decision-making, including measures of tumor growth. The CCP score is a quantitative, molecular measure of proliferation derived from the RNA expression of 31 cell cycle genes and a component of the molecular prognostic score (mPS). The mPS score is a linear combination of CCP score and pathological stage. CCP score and mPS are independent predictors of survival in resected lung adenocarcinoma. MATERIALS AND METHODS: CCP scores were determined by RT-qPCR for 318 patients diagnosed with stage I-II lung adenocarcinoma. Association of mPS and CCP score with distant recurrence and lung-cancer specific survival was assessed in Cox proportional hazards regression models adjusted for age, gender, tumor size, pathological stage and pleural invasion. Distant recurrence-free survival and lung-cancer specific survival by mPS risk group were calculated by Kaplan-Meier survival analysis. RESULTS: CCP scores were obtained for 205 stage I and 84 stage II patients. CCP score and mPS were independent markers of distant recurrence (CCP: HR 1.62, 95%CI 1.15-2.29, p=0.0055; mPS: HR 2.22, 95%CI 1.11-4.44, p=0.023). Patients with low mPS tumors were at significantly reduced risk of distant recurrence (log-rank p=4.2×10-5). Among stage I patients, stratification by mPS identified a patient group with increased risk of distant recurrence (36%, 95%CI 28-46%, log-rank p=0.0011) CONCLUSIONS: The molecular prognostic score stratifies early-stage, resected lung cancer patients for risk of distant recurrence and could be useful to inform treatment and surveillance decisions.

Prognostic factors in a multicentre study of 247 atypical pulmonary carcinoids.

OBJECTIVES: To analyse clinical and biomolecular prognostic factors associated with the surgical approach and the outcome of 247 patients affected by primary atypical carcinoids (ACs) of the lung in a multi-institutional experience. METHODS: We retrospectively evaluated clinical data and pathological tissue samples collected from 247 patients of 10 Thoracic Surgery Units from different geographical areas of our country. All patients were divided into four groups according to surgical procedure: sub-lobar resections (SURG1), lobar resections (SURG2), tracheobronchoplastic procedures (SURG3) and pneumonectomies (SURG4). Overall survival analysis was performed using the Kaplan-Meier method and log-rank test. Survival was calculated from the date of surgery to the last date of follow-up or death. The parameters evaluated included age, gender, smoking habits, laterality, type of surgery, 7th edition of TNM staging, mitosis Ki-67 (MIB1), multifocal forms, tumourlets, type of lymphadenectomy and neo/adjuvant therapy. For multivariate analysis, a Cox regression model was used with a forward stepwise selection of covariates. RESULTS: Two hundred and forty-seven patients (124 females and 123 males; range 10-84, median 60 years) underwent surgical resection for AC in the last 30 years as follows: n = 38 patients in SURG1, 181 in SURG2, 15 in SURG3 and 14 in SURG4. A smoking history was present in 136 of 247 (55%) patients. The median follow-up period was 98.7 (range 11.2-369.9) months. The overall survival probability analysis of the AC was 86.7% at 5 years, 72.4% at 10 years, 64.4% at 15 years and 58.1% at 20 years. Neuroendocrine multicentric forms were detected in 12 of 247 patients (4.8%; 1 of 12 pts) during the follow-up (range 11.2-200.4, median 98.7 months) and 33.4% had recurrence of disease. There were no significant differences between gender, tumour location and type of surgery at the multivariate analysis. Age [P < 0.001, hazard ratio (HR) 0.60; confidence interval (CI) 0.32-1.12], smoking habits (P = 0.002; HR 0.43, 95% CI 0.23-0.80) and lymph nodal metastatic involvement (P = 0.008; HR 0.46, 95% CI 0.26-0.82) were all significant at multivariate analysis. CONCLUSIONS: ACs of the lung are malignant neuroendocrine tumours with a worst outcome in patients over 70 years and in smokers. With the exception of pneumonectomy, the extent of resection does not seem to affect survival and should be accompanied preferably by lymphadenectomy. Pathological staging, along with a mitotic index more than Ki-67 (MIB1), appears to be the most significant prognostic factor at the univariate analysis.

Integrated FDG-PET/CT imaging is useful in the approach to carcinoid tumors of the lung.

BACKGROUND: Carcinoids enter the differential diagnosis of the solitary pulmonary nodule. Bronchial carcinoids have been traditionally considered as FDG-PET negative but recent studies have found an higher sensitivity of integrated FDG-PET/CT for the detection of these neoplasms. The purpose of this study was to investigate the value of integrated FDG-PET/CT for the evaluation of SPN suspected to be carcinoids. METHODS: All patients with pathologically proven bronchial carcinoids who had FDG-PET/CT scans between 2006 and 2012 have been retrospectively reviewed. PET/CT was performed with the same scanner and the same technique for all patients. The following data were retrieved: age, sex CT findings (side, location, size, shape, margins), SUVmax, type of operation, pathological findings (size and number of mitoses). Regarding PET findings, only SUVmax was considered, whereas the visual assessment was not undertaken. Carcinoids were defined as typical and atypical and as central and peripheral. The long-term follow-up was also recorded. The SUVmax was compared with the other clinical, radiological and pathological variables to find any significant difference or correlation. RESULTS: Twenty-five patients were retrieved, 24 typical and one atypical carcinoid, 21 peripheral and 4 central lesions. The mean diameter on CT-scan was 25.3 mm and the clinical size correlated well with the pathological size. Sixty percent of the tumors were ovoid and 68% had smooth margins. The mean SUVmax was 3.6 (range 1.4-12.9). All the lesions were completely resected. The regression analysis showed a direct correlation between the SUVmax and the tumor size (p = 0.004). No further correlations were found between the SUVmax and the other variables. None of the patients had recurrent disease or died during the follow-up. CONCLUSIONS: Our study showed that FDG-PET/CT might be a useful tool in the evaluation of SPNs suspected to be bronchial carcinoids. When a solitary pulmonary nodule shows an ovoid/round shape and smooth margins on the CT scan and demonstrates an FDG uptake higher than that of the normal lung and with a SUVmax value >1-1.5, a carcinoid should be suspected. If benign lesions can be presumably excluded, surgical resection or at least a biopsy of the lesion is recommended.

Preoperative predictors of successful surgical treatment in the management of parapneumonic empyema.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) and thoracotomy are the main surgical options for treating parapneumonic empyema. The choice of either operation depends on many preoperative features, including the patient's condition, clinical and radiologic findings, and pleural fluid characteristics. The identification of the combination of those preoperative findings that will allow surgeons to select the appropriate approach for a successful operation (VATS or thoracotomy) could be of great interest in clinical settings. METHODS: We retrospectively reviewed a series of 97 patients who had undergone successful VATS or thoracotomy for parapneumonic empyema; in all cases, the operation had begun through VATS and was changed to a thoracotomy if a complete decortication was needed. Preoperative clinical, radiologic, and laboratory features were compared between the two groups to search for differences that might serve as predictive factors for either operation. Perioperative findings were also analyzed. RESULTS: The operation was accomplished by VATS in 40 patients (41%), and conversion to thoracotomy was necessary in 57 (59%). Significant predictive factors for conversion were a prolonged delay from diagnosis to operation, the presence of fever and of pleural thickness on computed tomography (CT) images. The 25 patients who presented with these three features were cured by thoracotomy. The operative time and postoperative complication rate were significantly higher for the thoracotomy patients. CONCLUSIONS: Some preoperative features can help the surgeon to better select patients for the appropriate operation. Delayed operation, fever, and pleural thickness can be used to predict the likelihood of conversion to thoracotomy.

Prognostic role of clusterin in resected adenocarcinomas of the lung.

RATIONALE: Clusterin expression may change in various human malignancies, including lung cancer. Patients with resectable non-small cell lung cancer (NSCLC), including adenocarcinoma, have a poor prognosis, with a relapse rate of 30-50% within 5 years. Nuclear factor kB (Nf-kB) is an intracellular protein involved in the initiation and progression of several human cancers, including the lung. OBJECTIVES: We investigate the role of clusterin and Nf-kB expression in predicting the prognosis of patients with early-stage surgically resected adenocarcinoma of the lung. FINDINGS: The level of clusterin gradually decreased from well-differentiated to poorly differentiated adenocarcinomas. Clusterin expression was significantly higher in patients with low-grade adenocarcinoma, in early-stage disease and in women. Clusterin expression was inversely related to relapse and survival in both univariate and multivariate analyses. Finally, we observed an inverse correlation between Nf-kB and clusterin. CONCLUSIONS: Clusterin expression represents an independent prognostic factor in surgically resected lung adenocarcinoma and was proven to be a useful biomarker for fewer relapses and longer survival in patients in the early stage of disease. The inverse correlation between Nf-kB and clusterin expression confirm the previously reported role of clusterin as potent down regulator of Nf-kB.

Role of blebs and bullae detected by high-resolution computed tomography and recurrent spontaneous pneumothorax.

BACKGROUND: The prevention of recurrence after a first episode of primary spontaneous pneumothorax (PSP) remains a debated issue. The likelihood of recurrence based on the presence of blebs and bullae detected on high-resolution computed tomography (HRCT) imaging is controversial. METHODS: We evaluated patients conservatively treated for PSP who underwent chest HRCT scan in a single-institution retrospective longitudinal study. Absolute risk values and positive and negative predictive values of recurrence based on HRCT findings were the primary end points. RESULTS: We analyzed 176 patients. Ipsilateral and contralateral recurrence developed in 44.8% and 12% of patients, respectively. The risk of recurrence was significantly related to the presence of blebs or bullae, or both, at HRCT. The risk of ipsilateral recurrence for patients with or without blebs and bullae was 68.1% and 6.1%, respectively (positive predictive value, 68.1%; negative predictive value, 93.9%). The risk of contralateral pneumothorax for patients with or without blebs and bullae was 19% and 0%, respectively (positive predictive value, 19%; negative predictive value, 100%). The risk of ipsilateral recurrence was directly related to the dystrophic severity score: recurrence risk increased by up to 75% in patients with bilateral multiple lesions. Multivariate analysis showed that a positive HRCT was significantly related to ipsilateral recurrence. CONCLUSIONS: The presence of blebs and bullae at HRCT after a first episode of PSP is significantly related to the development of an ipsilateral recurrence or a contralateral episode of pneumothorax. Further studies are needed to validate the dystrophic severity score in the selection of patients for early surgical referral.

Enriched sera protein profiling for detection of non-small cell lung cancer biomarkers.

BACKGROUND: Non Small Cell Lung Cancer (NSCLC) is the major cause of cancer related-death. Many patients receive diagnosis at advanced stage leading to a poor prognosis. At present, no satisfactory screening tests are available in clinical practice and the discovery and validation of new biomarkers is mandatory. Surface Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-ToF-MS) is a recent high-throughput technique used to detect new tumour markers. In this study we performed SELDI-ToF-MS analysis on serum samples treated with the ProteoMiner™ kit, a combinatorial library of hexapeptide ligands coupled to beads, to reduce the wide dynamic range of protein concentration in the sample. Serum from 44 NSCLC patients and 19 healthy controls were analyzed with IMAC30-Cu and H50 ProteinChip Arrays. RESULTS: Comparing SELDI-ToF-MS protein profiles of NSCLC patients and healthy controls, 28 protein peaks were found significantly different (p < 0.05), and were used as predictors to build decision classification trees. This statistical analysis selected 10 protein peaks in the low-mass range (2-24 kDa) and 6 in the high-mass range (40-80 kDa). The classification models for the low-mass range had a sensitivity and specificity of 70.45% (31/44) and 68.42% (13/19) for IMAC30-Cu, and 72.73% (32/44) and 73.68% (14/19) for H50 ProteinChip Arrays. CONCLUSIONS: These preliminary results suggest that SELDI-ToF-MS protein profiling of serum samples pretreated with ProteoMiner™ can improve the discovery of protein peaks differentially expressed between NSCLC patients and healthy subjects, useful to build classification algorithms with high sensitivity and specificity. However, identification of the significantly different protein peaks needs further study in order to provide a better understanding of the biological nature of these potential biomarkers and their role in the underlying disease process.

N1 non-small-cell lung cancer. A 20-year surgical experience.

N1 non-small-cell lung cancer has heterogeneous prognosis in relation to node descriptors. There is no agreement on the ideal type of resection. A new classification of N1 descriptors was proposed in the 7(th) edition of the TNM staging system. A retrospective study was conducted on 384 patients with T1-T3N1 non-small-cell lung cancer who underwent complete pulmonary resection. The prognostic role of N1 descriptors according to the current and new staging systems and type of resection was investigated. The 5-year survival rate was 46%. Involvement of hilar node stations, multiple stations, and multiple nodes were poor prognostic factors (5-year survival, 33%, 21%, and 30%, respectively), as well as involvement of the hilar zone and multiple zones (5-year survival, 27% and 23%, respectively). Pneumonectomy showed significantly better survival rates compared to lobectomy or bilobectomy (5-year survival, 60% vs. 29%). Multivariate analysis showed that the number of N1 zones and type of resection were independent prognostic factors. Patients with hilar nodal, multiple-level, or multiple-zone involvement had poor prognosis. Standard lobectomy remains the procedure of choice, but in cases of fixed nodes in the hilar zone, sleeve resection or even pneumonectomy should be considered.

Primary pulmonary cancer colliding with metastatic breast carcinoma: hitherto unreported cases of cancer-to-cancer metastasis focusing on clinical implications.

Lung is one of the main sites of metastatic tumors, but collision neoplasms consisting of a primary lung cancer and metastatic breast carcinoma have never been so far reported. We describe here 2 cases of primary non-small cell lung cancers (squamous cell and adenocarcinoma, respectively) colliding with metastatic breast carcinomas (ductal and lobular carcinomas, respectively). Clinico-pathologic features characterizing this challenging diagnosis and the important therapeutic implications are discussed.

A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: clinicopathologic analysis, molecular features, and possible pitfalls in routine practice.

INTRODUCTION: Prognostic evaluation of bronchioloalveolar carcinoma (BAC) from a homogenous population of Caucasian patients. METHODS: Retrospective analysis of resected BAC reclassified according to the 2004 World Health Organization classification of lung tumors. Analyzed variables are clinicoradiologic presentation, histologic subtypes, stage, epidermal growth factor receptor (EGFR) and HER2/neu immunohistochemical expression, EGFR exons 18, 19, and 21 mutations, K-RAS exon 2 mutation. Univariate and multivariate analyses of survival were performed. RESULTS: Of 40 patients analyzed, EGFR and HER2/neu expression were detected in 72% and 20%, respectively. HER2/neu expression significantly characterized mucinous BAC (46% versus 7%; p = 0.014). EGFR mutations were identified in 17% (30% in nonmucinous BAC and none in mucinous BAC; p = 0.083). K-RAS mutations were found in 42.5% (92% in mucinous BAC versus 18% in other types; p 0.0001). Early stages (IA+IB) nonmucinous BAC had excellent prognosis: 5 years overall survival of 91% (100% for stage IA). Sixty six percent (4 of 6) of patients with multifocal disease died (two mucinous BAC and one nonmucinous BAC with recurrent disease). Seventy one percent (5 of 7) of patients with pneumonic-like tumor (all mucinous BAC) died of recurrent/progressive disease. Stage (p = 0.004) and histologic classifications (p = 0.035) resulted as independent prognostic factors at multivariate analysis. CONCLUSIONS: Early stage nonmucinous BAC has excellent prognosis, whereas mucinous BAC presents a poor prognosis. Locally advanced nonmucinous BAC has a poor prognosis: the diagnosis of nonmucinous BAC in large tumors should be interpreted with caution given the possible presence of invasive areas in incompletely sampled tumor. Coexpression of EGFR and HER2/neu in mucinous BAC could be considered for future trials on target therapies even in Caucasian population.

Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy.

Adipose-derived mesenchymal stromal/stem cells (AD-MSC) may offer efficient tools for cell-based gene therapy approaches. In this study, we evaluated whether AD-MSC could deliver proapoptotic molecules for cancer treatment. Human AD-MSCs were isolated and transduced with a retroviral vector encoding full-length human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a proapoptotic ligand that induces apoptosis in a variety of human cancers but not normal tissues. Although several studies have documented the antitumor activity of recombinant human TRAIL, its use in vivo is limited by a short half-life in plasma due to a rapid clearance by the kidney. We found that these limitations can be overcome using stably transduced AD-MSC, which could serve as a constant source of TRAIL production. AD-MSC armed with TRAIL targeted a variety of tumor cell lines in vitro, including human cervical carcinoma, pancreatic cancer, colon cancer, and, in combination with bortezomib, TRAIL-resistant breast cancer cells. Killing activity was associated with activation of caspase-8 as expected. When injected i.v. or s.c. into mice, AD-MSC armed with TRAIL localized into tumors and mediated apoptosis without significant apparent toxicities to normal tissues. Collectively, our results provide preclinical support for a model of TRAIL-based cancer therapy relying on the use of adipose-derived mesenchymal progenitors as cellular vectors.

Atypical carcinoid with prominent mucinous stroma: a hitherto unreported variant of pulmonary neuroendocrine tumor.

Carcinoid tumors of the lung may show several growth patterns and cell types. We report here a previously undescribed case of primary pulmonary atypical carcinoid with prominent mucinous stroma, an exceedingly rare variant of carcinoid tumor so far reported only in the thymus. The tumor was discovered in a 50-year-old, non-smoker woman, and pursued an aggressive behavior. The lack of TTF-1 expression and the positive staining with hormonal receptors made the diagnosis very challenging. Differential diagnosis with other primary and metastatic mucin-rich tumors is also discussed.

The variation of prognostic significance of Maximum Standardized Uptake Value of [18F]-fluoro-2-deoxy-glucose positron emission tomography in different histological subtypes and pathological stages of surgically resected Non-Small Cell Lung Carcinoma.

Even if the prognostic role of SUVmax of 18-FDG-PET has been largely investigated, many issues regarding its relationship with pathologic staging and histological subtypes still remain controversial. This retrospective study investigated the prognostic significance of SUVmax in 119 completely resected, pathologically proven NSCLC. The SUVmax values resulted significantly related to histological subtypes (p<0.001), histological grading (p<0.001), and pathologic stage (p<0.001). The optimal cut-off value of SUVmax to predict prognosis in the whole series was 6.7 (p=0.029). 2-Year disease-specific survival (DSS) was 91% for SUVmax < or =6.7 and 55% for SUVmax >6.7 (p<0.001). SUVmax still remain a significant predictor of survival in Stage IB (2-year DSS of 100% for SUVmax < or =6.7; 51% for SUVmax >6.7, p=0.016). The optimal cut-off values of SUVmax to predict prognosis were 5 for adenocarcinoma (p=0.027) and 10.7 for other non-adenocarcinoma NSCLC subtypes (p=0.010). These histologic-specific cut-offs resulted significantly related to survival when stratified for stage: 2-year DSS for Stage IB adenocarcinoma were 100% for SUV< or =5 and 40% for SUVmax >5 (p=0.051); 2-year DSS for Stage IB non-adenocarcinoma were 83% for SUVmax < or =10.7 and 26% for SUVmax >10.7 (p=0.018). Adenocarcinomas showed significantly lower survival results respect to other NSCLC for intermediate SUVmax level (range 5.5-11.3) (p=0.021). High SUVmax resulted an independent negative prognostic factor at multivariate analysis (HR of 15.7, 95% CI of 2.50-98.44, p=0.003). In conclusion, SUVmax represents a significant prognostic factor in surgically resected NSCLC but a great variability between different histological subtypes, even when adjusted for stage, is present and could be considered when planning future trials on prognostic role of FDG uptake.

Long-term functional results after surgical treatment of parapneumonic thoracic empyema.

Retrospective evaluation of long-term functional results of surgical treatment of chronic pleural empyema. Two different surgical procedures (debridement vs. decortication) and approaches (VATS vs. thoracotomy) were analyzed. Three end-points were considered: short-term surgical results, short- and long-term radiological results, clinico-functional long-term results. Fifty-one debridement (52% VATS, 48% thoracotomy) and 68 decortication were performed. Postoperative mortality and morbidity were 1.5% and 24%, respectively. Older age (>70 years old) had worse postoperative morbidity (P=0.048). Video-assisted thoracic surgery (VATS) debridement had lower postoperative hospital stay (P=0.006) and shorter duration of chest drainage (P=0.006). The infectious process was resolved in all patients. All patients presented a postoperative radiological improvement, 63 patients (60%) with a complete pulmonary re-expansion. Sixty patients (58%) referred a complete respiratory recovery. VATS debridement had a greater improvement in subjective dyspnea degree (P=0.041). The long-term spirometric evaluation was normal in 58 patients (56%). Age >70 years old resulted the only variable associated to poor long-term results (FEV(1)% < 60% and/or MRC grade > or = 2) at multivariate analysis. Surgical treatment of pleural empyema achieves excellent long-term respiratory outcomes. VATS is associated to less postoperative mortality and shorter postoperative hospital stay. In elderly patients, postoperative morbidity could be higher and long-term functional improvement less warranted.

Double synchronous pulmonary lymphatic-related lesions.

A wide range of pathologies may primarily affect the lymphatic vessels in the lungs. In this article, a unique case of pulmonary silicosis associated with a subtle lymphangitic carcinomatosis from an unknown prostate cancer is reported and discussed.

Unusual pathogenesis of spontaneous pneumothorax secondary to Wegener's granulomatosis.

Spontaneous pneumothorax represents a rare and potentially severe complication of Wegener's granulomatosis. A 31-year-old man with Wegener's granulomatosis on immunosuppressive therapy was admitted for a right massive spontaneous pneumothorax. After chest drainage he presented with a prolonged air leak that required a surgical treatment. Histologic findings did not reveal any necrotizing granulomatous vasculitis, but only subpleural fibrous tissue. We hypothesize that pneumothorax could be related to the subpleural fibrous retraction induced by immunosuppressive therapy.

Bronchial typical carcinoid tumors.

The current WHO classification of lung tumors recognizes bronchial typical carcinoid as low-grade neuroendocrine tumors. These tumors grow slowly but can metastasize to regional nodes (4 to 20%) and more rarely to extrathoracic sites. Symptoms are usually related to local compression and obstruction of the bronchial tree. Paraneoplastic syndrome can be present (carcinoid syndrome, Cushing's syndrome, acromegaly). Preoperative diagnosis is usually obtained with bronchoscopic biopsy. Computed tomography and somatostatin receptor scintigraphy are useful in the preoperative staging. Only selected cases can be treated endoscopically with laser resection. The complete surgical resection remains the only therapy with curative intent in the majority of patients. Parenchyma-sparing resections are indicated whenever possible. Overall survival after surgery is excellent (5-year rate, 87 to 100%) with low recurrence rate (2 to 11%). N-status and type of resection seem not to affect prognosis. Local relapse can be treated successfully with surgery, whereas distant metastases have a poor prognosis even after chemotherapy.