Prevention of systemic toxicity in hyperthermic isolated lung perfusion using radioisotopic leakage monitoring.

RATIONALE: Hyperthermic isolated lung Perfusion (ILuP) is used to deliver high-dose chemotherapy to pulmonary metastases while sparing systemic toxicity. Accurate leakage monitoring is however necessary. This study aimed to verify the accuracy of radionuclide leakage monitoring in patients undergoing ILuP, by comparing this method with serial blood sampling. METHODS: A total of 15 consecutive ILuP procedures were performed on eleven patients affected by lung metastases from soft tissue sarcoma. After establishing isolated perfusion, erythrocytes of systemic blood (SB) were labelled with 0.2 MBq/kg of 99mTc. The baseline SB counting rate (CR) was assessed using a γ-probe. Subsequently, erythrocytes of the circuit blood (CB) were labelled with 2 Mbq/kg of 99mTc. Radioactivity leakage factor (RLF) was continuously measured using a formula, accounting for CR, systemic/circuit activity ratio and total/systemic volume ratio. The TNF-α concentration in SB and CB was measured by enzymelinked immunosorbent assay (ELISA) throughout the procedure. RESULTS: RLF averaged 2.3 ± 1.5%, while the systemic/circuit TNF-α ratio was 0.05 ± 0.12%. These two indices were strictly correlated in all of the procedures (average Rvalue 0.88 ± 0.07). RLF exceeded 5% during three of 15 procedures, prompting the application of compensatory manoeuvres. ELISA confirmed a marked increase in systemic TNF-α levels in these patients (2.6 ± 3.5 ng/ml). Conversely, patients whose RLF did not exceed the 5% threshold presented a mean TNF-α of 0.02 ± 0.005 ng/ml (p < 0.01). CONCLUSIONS: In patients submitted to ILuP, RLF monitoring is feasible and accurate. Moreover, it grants immediate results, permitting for the adoption of corrective manoeuvres for leakage, thus minimising toxicity.

Pleural lavage cytology predicts recurrence and survival, even in early non-small cell lung cancer.

PURPOSE: The TNM staging remains the best prognostic descriptor of lung cancer; however, new independent prognostic factors are needed, particularly for early stage disease. METHODS: An evaluation of the pleural lavage cytology (PLC) was performed in 436 consecutive NSCLC patients who underwent surgical resection; clinical, pathological and follow-up data were available for 414 patients. RESULTS: The PLC was positive in 15 patients (3.6 %). The overall five-year survival was 35.9 % in PLC-positive and 57.8 % in PLC-negative patients (p = 0.004). To compare groups with the same prognostic characteristics, the analysis was restricted to p-stage I patients, but the survival remained worse in the PLC-positive patients (42.9 vs 69.4 %; p = 0.001). Recurrence was also observed more frequently in PLC-positive cases: 69.2 vs 34.5 %, OR 4.28 (95 % CI 1.29-14.18; p = 0.01). Among the PLC-positive patients, no difference between the local (44.4 %) and distant (55.6 %) relapse patterns was found (p = 0.82). The multivariate analysis identified four independent prognostic factors: age (p < 0.001), disease stage (p < 0.001), gender (p = 0.025) and PLC status (p = 0.012). CONCLUSIONS: PLC is an independent prognostic factor for NSCLC. PLC-positive NSCLC patients have a worse overall survival and a higher recurrence rate, even in stage I disease. PLC-positive patients should be considered a high risk category, who should potentially be eligible for adjuvant therapy regardless of their p-stage.

Glyceraldehyde-3-phosphate dehydrogenase gene over expression correlates with poor prognosis in non small cell lung cancer patients.

BACKGROUND: Glycolysis in presence of oxygen with high glucose consumption is known to be the metabolism of choice in many tumors. In lung cancer this phenomenon is routinely exploited in diagnostic PET imaging of fluorodeoxyglucose uptake, but not much is known about the prognostic capabilities of glycolysis level assessment in resected lung tumor samples. METHODS: In this retrospective study, we used real time polymerase chain reaction(RQ-PCR) to assess the expression level of the gene for Glyceraldehyde 3-phosphate dehydrogenase(GAPDH), key enzyme for glucose breakdown, in tumor samples from 82 consecutive early stages resected non small cell lung cancer(NSCLC) patients. We then compared our results in six large publicly available NSCLC microarray datasets collecting data from over 1250 total patients. RESULTS: In our study GAPDH gene over expression was found to be an adverse prognostic factor in early stages NSCLC (n = 82 HR = 1.30 p = 0.050). This result was confirmed in 5 of 6 public datasets analyzed: Shedden et al. 2008: n = 442 HR = 1.54 p < 0.0001; Lee et al. 2008: n = 138 HR = 1.31 p = 0.043; Tomida et al. 2009: n = 117 HR = 1.59 p = 0.004; Roepman et al. 2009: n = 172 (TPI1 gene) HR = 1.51 p = 0.009; Okayama et al. 2012: n = 226 HR = 3.19 p < 0.0001; Botling et al. 2013: n = 196 HR = 1.00 p = 0.97). Furthermore, in the large and clinically well annotated Shedden et al. microarray dataset, GAPDH hazard ratio did not change whether calculated for the whole dataset or for the subgroup of adjuvant naive patients only (n = 330 HR = 1.49 p < 0.0001). CONCLUSION: GAPDH gene over expression in resected tumor samples is an adverse prognostic factor in NSCLC. Our results confirm the prognostic value of glucose metabolism assessment in NSCLC.

Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer.

The role of CTLA-4 in negative regulation of T-cell mediated immune response is particularly well established. Much less is known about its expression and function in tumour cells, and to our knowledge, no data are available on its possible impact on prognosis of NSCLC patients. We investigated CTLA-4 expression and prognostic role in 81 patients with radically resected stage I-III NSCLC. The analysis was performed by tissue microarray immunohistochemistry, and the median H-score of 20 was used as a threshold to define CTLA-4 overexpressing tumours. Correlation with standard prognostic factors was performed by using absolute and relative fold change indexes. Hazard ratios (HR) and corresponding 95% confidence limits (95% CL) were computed through the Cox model. A higher frequency of CTLA-4 overexpression (>20) was found in non-squamous than in squamous NSCLC (52.8 vs. 35.7%) and in Ki67 ≤ 15 expressing tumours, as compared to those with Ki67 > 15 (51.5 vs. 38.7%). A reduced death rate was found in CTLA-4 overexpressing tumours (HR = 0.60, 95% CL = 0.28/1.23), and a further decrease was observed when considering tumours with CTLA-4 > 20 and Ki67 ≤ 15, in comparison with tumours with CTLA-4 ≤ 20 and Ki67 > 15 (HR = 0.41; 95% CL = 0.15/1.13). Our observational and exploratory study provides a first and promising indication for an independent prognostic effect of CTLA-4 overexpression in radically resected NSCLC. We presume that this effect relies on modulation of the interaction of microscopic disease with CTLA-4-ligands expressing cells leading to NSCLC cell death.

External validation of the N descriptor in the proposed tumour-node-metastasis subclassification for lung cancer: the crucial role of histological type, number of resected nodes and adjuvant therapy.

OBJECTIVES: Overlapping survival curves for N1b (multiple N1 stations), N2a2 (single N2 station + N1 involvement) and N2a1 (skip N2 metastasis) limit the current tumour-node-metastasis (TNM) node (N) subclassification for node involvement. We validated externally the proposed subclassification. METHODS: Clinical records from a multicentric database comprising 1036 patients with pulmonary adenocarcinoma (ADC) or squamous cell carcinoma with N1/N2 involvement who underwent, from January 2002 to December 2014, complete lung resections were retrospectively reviewed. Patients were categorized according to the 8th TNM N subclassification proposal. Histological type, number of resected nodes (#RN) and adjuvant therapy (ADJ) were considered limiting factors. RESULTS: No difference in the 5-year overall survival (-OS) was noted between N1b and N2a1 (49.6% vs 44.8%, P = 0.72); instead, the 5-year-OS was significantly improved in patients with squamous cell carcinoma (63% in N1b vs 30.7% in N2a1, P = 0.04). In patients with ADC, the 5-year-OS was better in those with N2a1 than with N1b (50.6% vs 37.5%, P = 0.09). When we compared N1b with N2a2, the 5-year-OS was statistically significant (49.6% vs 32.8%, P = 0.02); considering only patients with squamous cell carcinoma (63% vs 25.8%, P = 0.003), #RN >10 (63.2% vs 35.3%, P = 0.05) and without ADJ (56.4% vs 24.5%, P = 0.02), the 5-year-OS was significantly different. Differences were not significant for ADC, #RN <10 and ADJ. Finally, the 5-year-OS was statistically significant when we compared N2a1 with N2a2 of the total cohort (44.8% vs 32.8%, P = 0.04), in ADC (5-year-OS 50.6% vs 36.5%, P = 0.04) and #RN >10 (5-year-OS 49.8% vs 32.1%, P = 0.03) without ADJ. CONCLUSIONS: Histological type, ADJ and #RN are relevant prognostic factors in N + non-small-cell lung cancer. Considering these results, we may better interpret the prognosis prediction limits of the proposed 8th TNM subclassification for the N descriptor.

Mediastinal Up-Staging During Surgery in Non-Small-Cell Lung Cancer: Which Mediastinal Lymph Node Metastasis Patterns Better Predict The Outcome? A Multicenter Analysis.

BACKGROUND: Unexpected N2 involvement occurs in approximately 10% to 20% of patients with non-small-cell lung cancer (NSCLC) and patients' prognostic factors remain unclear. The aim of this study was to evaluate prognostic factors in these patients. METHODS: From January 2002 to December 2012, we retrospectively analyzed data of 550 patients with NSCLC with preoperative negative, but pathologic positive N2 involvement, who underwent anatomical lung resection and hilo-mediastinal lymphadenectomy, obtained from 6 institutions. An established prognostic factor panel and N2-type involvement were correlated to overall (OS), cancer-specific (CSS), and disease-free survival (DFS) using multivariate Cox Regression model. The following lymph node patterns were analyzed: number of resected nodes (#RNs), metastatic nodes (#MNs), ratio between #MNs and #RNs (NR), N2 subgroups proposed for the eighth TNM edition, and lobe-specific versus nonspecific metastasis. RESULTS: Regarding our cohort, 419 patients were staged IIIA (T1-2N2), 131 IIIB (T3-4 N2), 113 pT1, 306 pT2, 94 pT3, and 37 pT4; 5-year OS, DFS, and CSS were 34.1%, 20.1%, and 64.6%, respectively. Independent prognostic factor for OS, in the multivariable analysis, were as follows: NR <17% (P = .009), proposed N2 classification subgroups (P = .014), age <66 (P < .001), and pT (P = .005); for DFS: NR <17% (P = .003), adjuvant treatment (P = .026), and pT (P = .026); and for CSS: NR <17% (P = .008), grading (P = .001), and adjuvant treatment (P < .001). CONCLUSION: Our study confirms that adjuvant therapy is fundamental and NR, in patients with unexpected N2 involvement, has a strong prognostic factor. In particular, a NR cutoff value of 17% could predict OS, DFS, and CSS in patients with NSCLC.

Lymph-node ratio predicts survival among the different stages of non-small-cell lung cancer: a multicentre analysis†.

OBJECTIVES: The prognostic role of the number of resected and metastatic lymph nodes in non-small-cell lung cancer (NSCLC) is still being debated. The aim of this study was to evaluate the impact of lymphadenectomy in addition to the already validated variables in NSCLC survival. METHODS: From January 2002 to December 2012, data on 4858 patients with NSCLC undergoing anatomical lung resection and hilomediastinal lymphadenectomy in 6 institutions were analysed retrospectively. Established prognostic factors in addition to the number of resected lymph nodes and the ratio between the number of metastatic lymph nodes and the number of resected lymph nodes (NR) were correlated to overall survival (OS) and disease-free survival (DFS) using the multivariable Cox regression model. Harrell's C-statistic with the 95% confidence interval (CI) was determined. Analysis by means of maximally selected log-rank statistics was performed to find optimal cut-off points in order to split patients into groups with different outcome probabilities. RESULTS: The median numbers of resected lymph nodes and of metastatic lymph nodes were 17 (range 6-85) and 2 (1-36), respectively. Hilar (N1) and mediastinal (N2) metastases were identified in 21.3% and 20.0% of cases, respectively. Overall, the 5-year OS and DFS rates were 54.6% and 44.8%, respectively. At multivariable analysis, age, gender, pathological stage, R0 resection, type of surgery and NR correlated with longer OS rates; the same variables plus tumour grading were further related to DFS. C-statistics were 66.0 (95% CI 62.7-69.4) for DFS and 60.5 (95% CI 58.3-62.6) for OS. An NR <40% significantly correlated with a higher 5-year survival rate in the total sample (OS 57.6% vs 23.8%, P < 0.001; DFS 48.2% vs 11.4, P < 0.001) and in patients with N1 (OS 47.9% vs 36.1%, P = 0.03; DFS 39% vs 24.2%, P = 0.02) and N2 (OS 36.9% vs 21.8%, P < 0.001 DFS 23.9% vs 9.1%, P < 0.001). CONCLUSIONS: Our study confirms that the number of resected lymph nodes is a strong prognostic indicator in NSCLC. In particular, an NR cut-off value of 40% may predict both OS and DFS.

Prognostic Model for Resected Squamous Cell Lung Cancer: External Multicenter Validation and Propensity Score Analysis exploring the Impact of Adjuvant and Neoadjuvant Treatment.

INTRODUCTION: We developed one of the first clinicopathological prognostic nomograms for resected squamous cell lung cancer (SQLC). Herein, we validate the model in a larger multicenter cohort and we explore the impact of adjuvant and neoadjuvant treatment (ANT). METHODS: Patients with resected SQLC from January 2002 to December 2012 in six institutions were eligible. Each patient was assigned a prognostic score based on the clinicopathological factors included in the model (age, T descriptor according to seventh edition of the TNM classification, lymph node status, and grading). Kaplan-Meier analysis for disease-free survival, cancer-specific survival (CSS), and overall survival was performed according to a three-class risk model. Harrell's C-statistics were adopted for model validation. The effect of ANT was adjusted with propensity score. RESULTS: Data on 1375 patients were gathered (median age, 68 years; male sex, 86.8%; T descriptor 1 or 2 versus 3 or 4, 71.7% versus 24.9%; nodes negative versus positive, 53.4% versus 46.6%; and grading of 1 or 2 versus 3, 35.0% versus 41.1%). Data for survival analysis were available for 1097 patients. With a median follow-up of 55 months, patients at low risk had a significantly longer disease-free survival than did patients at intermediate risk (hazard ratio [HR] = 1.67, 95% confidence interval [CI]: 1.40-2.01) and patients at high risk (HR = 2.46, 95% CI: 1.90-3.19); they also had a significantly longer CSS (HR = 2.46, 95% CI: 1.80-3.36 versus HR = 4.30, 95% CI: 2.92-6.33) and overall survival (HR = 1.79, 95% CI: 1.48-2.17 versus HR = 2.33, 95% CI: 1.76-3.07). A trend in favor of ANT was observed for intermediate-risk/high-risk patients, particularly for CSS (p = 0.06 [5-year CSS 72.7% versus 60.8%]). CONCLUSIONS: A model based on a combination of easily available clinicopathological factors effectively stratifies patients with resected SQLC into three risk classes.

Pleurectomy-decortication in malignant pleural mesothelioma: are different surgical techniques associated with different outcomes? Results from a multicentre study.

OBJECTIVES: The potential benefit of surgery for malignant pleural mesothelioma (MPM), especially concerning pleurectomy/decortication (P/D), is unclear from the literature. The aim of this study was to evaluate the outcome after multimodality treatment of MPM involving different types of P/D and to analyse the prognostic factors. METHODS: We reviewed 314 patients affected by MPM who were operated on in 11 Italian centres from 1 January 2007 to 11 October 2014. RESULTS: The characteristics of the population were male/female ratio: 3.7/1, and median age at operation was 67.8 years. The epithelioid histotype was observed in 79.9% of patients; neoadjuvant chemotherapy was given to 57% of patients and Stage III disease was found following a pathological analysis in 62.3% of cases. A total of 162 (51.6%) patients underwent extended P/D (EP/D); 115 (36.6%) patients had P/D and 37 (11.8%) received only a partial pleurectomy. Adjuvant radiotherapy was delivered in 39.2% of patients. Median overall survival time after surgery was 23.0 [95% confidence interval (CI): 19.6-29.1] months. On multivariable (Cox) analysis, pathological Stage III-IV [ P = 0.004, hazard ratio (HR):1.34; 95% CI: 1.09-1.64], EP/D and P/D ( P = 0.006, HR for EP/D: 0.46; 95% CI: 0.29-0.74; HR for P/D: 0.52; 95% CI: 0.31-0.87), left-sided disease ( P = 0.01, HR: 1.52; 95% CI: 1.09-2.12) and pathological status T4 ( P = 0.0003, HR: 1.38; 95% CI: 1.14-1.66) were found to be independent significant predictors of overall survival. CONCLUSIONS: Whether the P/D is extended or not, it shows similarly good outcomes in terms of early results and survival rate. In contrast, a partial pleurectomy, which leaves gross tumour behind, has no impact on survival.

Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer.

Indoleamine 2,3-dioxygenase (IDO), a catabolizing enzyme of tryptophan, is supposed to play a role in tumor immune escape. Its expression in solid tumors has not yet been well elucidated: IDO can be expressed by the tumor cells themselves, or by ill-defined infiltrating cells, possibly depending on tumor type. We have investigated IDO expression in 25 cases of non-small cell lung cancer (NSCLC). Using histochemistry and immunohistochemistry, we found that IDO was expressed not by tumor cells, but by normal cells infiltrating the peritumoral stroma. These cells were neither macrophages nor dendritic cells, and were identified as eosinophil granulocytes. The amount of IDO-positive eosinophils varied in different cases, ranging from a few cells to more than 50 per field at x200 magnification. IDO protein in NSCLC was enzymatically active. Therefore, at least in NSCLC cases displaying a large amount of these cells in the inflammatory infiltrate, IDO-positive eosinophils could exert an effective immunosuppressive action. On analyzing the 17 patients with adequate follow-up, a significant relationship was found between the amount of IDO-positive infiltrate and overall survival. This finding suggests that the degree of IDO-positive infiltrate could be a prognostic marker in NSCLC.

Pulmonary middle lobectomy for non-small-cell lung cancer: effectiveness and prognostic implications.

OBJECTIVES: The therapeutic value of pulmonary middle lobectomy (PML) has been questioned. PML is currently regarded as a standard form of lobectomy, even so it shares some surgical features with segmentectomies (SEG) more than with lobectomies. The present study's aim was to assess the therapeutic value of PML with respect to other lobectomies (LOBs) and SEGs. METHODS: A total of 902 consecutive patients who underwent lobectomy or SEG with mediastinal lymph node dissection for Stage I-IIIa non-small-cell lung cancer were analysed. Patients with pT4 tumours and/or pathologically incomplete resection were excluded. RESULTS: PML was performed in 50 patients, SEG in 44 and LOBs were performed in 808. The three study groups were homogeneous, except for gender, pT and grade: females, pT1 and G1 tumours were more frequent in the PML and SEG groups. The lymph node dissection yield was poorer in PML (P < 0.007) and SEG (P < 0.001) groups when compared with LOB group. Five-year overall survival (OS) was 45.3% for PML, 54.0% for SEG and 60.2% for LOB (P = 0.793). When limiting the analysis to G2-3 right-sided tumours, 5-year survival was lower in the PML group than in the LOB group: 41.3 vs 59.0% (P = 0.057). Similar results were found when analysing pT2-3 right-sided tumours: 27.3 vs 57.3% (P = 0.049). Multivariable analysis showed four independent prognostic factors: age (P = 0.001), pathological stage (P < 0.001), gender (P = 0.005) and the type of surgical resection (P = 0.029). PML (hazard ratio, HR = 1.63) and SEG (HR = 1.64) were detrimental in comparison with LOB. After adjusting for baseline differences between groups (propensity score), a trend towards a worse OS in PML group when compared with LOB group was observed (HR = 1.38, P = 0.150). CONCLUSIONS: Both the lymphadenectomy yield and prognosis make PML more similar to SEG than lobectomy, especially for pT2-3 or G2-3 tumours.

Temporal trend, geographic distribution, and publication quality in asbestos research.

Asbestos is a well-known cause of cancer and respiratory diseases. The aim of the current study was to investigate the scientific production in asbestos research evaluating temporal trend, geographic distribution, impact factor (IF) of published literature, and taking into account socioeconomic variables. The PubMed database was searched starting from 1970. Publication numbers and IF were evaluated as absolute values and after standardization by population and gross domestic product (GDP). Six thousand nine hundred seven articles related to asbestos were retrieved. Publications grew steeply in the 1970s, leveled off in the 1980s, decreased in the 1990s, and then increased again. Mesothelioma, lung neoplasms, and occupational diseases are the most commonly used keywords. In the period of 1988-2011, 4220 citations were retrieved, 3187 of whom had an impact factor. The US, Italy, and the UK were the most productive countries. European countries published about 20 % more asbestos-related articles than the US, although the latter reached a higher mean IF, ranking second after Australia. When the national scientific production (sum of IF) was compared taking into account socioeconomic variables, Australia and Scandinavian countries performed very well, opposite to all main asbestos producers like Russia, China, and Brazil (except for Canada). The American Journal of Industrial Medicine and the Italian La Medicina del Lavoro published the highest numbers of articles. This study provides the first bibliometric analysis of scientific production in asbestos research. Interest appears to be higher in selected countries, with strong national features, and is growing again in the new millennium.

Expression of Ribonucleotide Reductase Subunit-2 and Thymidylate Synthase Correlates with Poor Prognosis in Patients with Resected Stages I-III Non-Small Cell Lung Cancer.

Biomarkers can help to identify patients with early-stages or locally advanced non-small cell lung cancer (NSCLC) who have high risk of relapse and poor prognosis. To correlate the expression of seven biomarkers involved in DNA synthesis and repair and in cell division with clinical outcome, we consecutively collected 82 tumour tissues from radically resected NSCLC patients. The following biomarkers were investigated using IHC and q RT-PCR: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2), subunit p53R2, thymidylate synthase (TS), and class III beta-tubulin (TUBB3). Gene expression levels were also validated in an available NSCLC microarray dataset. Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS). Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours. For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels. The NSCLC microarray dataset showed RRM2 and TS as biomarkers significantly associated with OS. This study suggests that high expression levels of RRM2 and TS might be negative prognostic factors for resected NSCLC patients.

Prognostic Score of Long-Term Survival After Surgery for Malignant Pleural Mesothelioma: A Multicenter Analysis.

BACKGROUND: Despite ongoing efforts to improve therapy in malignant pleural mesothelioma, few patients undergoing extrapleural pneumonectomy experience long-term survival (LTS). This study aims to explore predictors of LTS after extrapleural pneumonectomy and to define a prognostic score. METHODS: From January 2000 to December 2010, we retrospectively reviewed clinicopathologic and oncological factors in a multicenter cohort of 468 malignant pleural mesothelioma patients undergoing extrapleural pneumonectomy. LTS was defined as survival longer than 3 years. Associations were evaluated using χ(2), Student's t, and Mann-Whitney U tests. Logistic regression, Cox regression hazard model, and bootstrap analysis were applied to identify outcome predictors. Survival curves were calculated by the Kaplan-Meier method. Receiver operating characteristic analyses were used to estimate optimal cutoff and area under the curve for accuracy of the model. RESULTS: Overall, 107 patients (22.9%) survived at least 3 years. Median overall, cancer-specific, and disease-free survival times were 60 (95% confidence interval [CI], 51 to 69), 63 (95% CI, 54 to 72), and 49 months (95% CI, 39 to 58), respectively. At multivariate analysis, age (odds ratio, 0.51; 95% CI, 0.31 to 0.82), epithelioid histology (odds ratio, 7.07; 95% CI, 1.56 to 31.93), no history of asbestos exposure (odds ratio, 3.13; 95% CI, 1.13 to 8.66), and the ratio between metastatic and resected lymph nodes less than 22% (odds ratio, 4.12; 95% CI, 1.68 to 10.12) were independent predictors of LTS. According to these factors, we created a scoring system for LTS that allowed us to correctly predict overall, cancer-specific, and disease-free survival in the total sample, obtaining two different groups with favorable or poor prognosis (area under the curve, 0.74; standard error, 0.04; p < 0.0001). CONCLUSIONS: Our prognostic model facilitates the prediction of LTS after surgery for malignant pleural mesothelioma and can help to stratify the outcome and, eventually, tailor postoperative treatment.

Does surgery improve survival of patients with malignant pleural mesothelioma?: a multicenter retrospective analysis of 1365 consecutive patients.

BACKGROUND: Surgery with pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) can be an option for selected patients with resectable malignant pleural mesothelioma (MPM). The aim of this study was to investigate the impact of surgical treatment on the outcome of patients with MPM. METHODS: We retrospectively reviewed data from 1365 consecutive patients with histologically proven MPM, treated from 1982 to 2012 in six Institutions. Patients received chemotherapy alone (n = 172), best supportive care (n = 690), or surgical treatment (n = 503), by either P/D (n = 202) or EPP (n = 301) with or without chemotherapy. RESULTS: After a median follow-up of 6.7 years (range, 1.1-14.8), 230 patients (16.8%) were alive; median survival for patients who received palliative treatment or chemotherapy alone, P/D, and EPP were 11.7 (95% CI, 10.5-12.5), 20.5 (95% CI, 18.2-23.1), and 18.8 (95% CI, 17.2-20.9) months, respectively. The 30-day mortality was 2.6% after P/D and 4.1% after EPP (p = 0.401). According to multivariate analysis (n = 1227), age less than 70, epithelial histology, and chemotherapy were independent favorable prognostic factors. In the subset of 313 patients (25.5%) with all favorable prognostic factors, median survival was 18.6 months after medical therapy alone, 24.6 months after P/D, and 20.9 months after EPP (p = 0.596). CONCLUSIONS: Our data suggest that patients with good prognostic factors had a similar survival whether they received medical therapy only, P/D, or EPP. The modest benefit observed after surgery during medical treatment requires further investigation, and a large multicenter, randomized trial, testing P/D after induction chemotherapy versus chemotherapy alone in MPM patients with good prognostic factors, is needed.

Extrapleural pneumonectomy for malignant mesothelioma: an Italian multicenter retrospective study.

BACKGROUND: This study assessed perioperative outcome and long-term survival in a large series of patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy (EPP) to identify prognostic factors allowing better patient selection. METHODS: We retrospectively collected data from nine referral centers for thoracic surgery in Italy. Perioperative outcome and survival data were available for 518 malignant pleural mesothelioma patients (84.4% with epithelial tumors, 68.0% with pathologic stage 3 disease) who underwent EPP with intention-to-treat (R0/R1) between 2000 and 2010. Induction chemotherapy was administered in 271 patients (52.3%) and adjuvant therapy in 373 patients (72.0%), including radiotherapy in 213 patients (41.1%), adjuvant chemotherapy in 43 patients (8.3%), and both in 117 patients (22.6%). RESULTS: In all, 136 patients (26.3%) had major complications after EPP, and 36 (6.9%) died within 90 days after surgery. The median overall survival was 18 months, with a 1-, 2-, and 3-year overall survival of 65%, 41%, and 27%, respectively. At multivariable analysis adjusted for age and disease stage, male sex (hazard ratio [HR] 1.47, 95% confidence interval [CI]: 1.12 to 1.92), nonepithelial histology (HR 1.96, 95% CI: 1.48 to 2.58), and trimodality treatment using induction chemotherapy (HR 0.61, 95% CI: 0.43 to 0.85) were significantly associated with survival. Development of a major complication also significantly worsened outcome (HR 1.85, 95% CI: 1.37 to 2.50). CONCLUSIONS: The success of EPP in the context of a multimodality treatment depends on a series of patient characteristics. Female patients, patients with epithelial tumors, and patients who received induction chemotherapy will best benefit from EPP.

Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: a tissue micro array-based multicenter study.

OBJECTIVES: Tumor angiogenesis is an essential and complex process necessary for the growth of all tumors which represents a potential therapeutic target. Angiogenesis inhibitors targeting vascular endothelial growth factor (VEGF) or their receptor tyrosine kinases have been approved by the FDA. In thymic epithelial tumors (TET), targeted therapies have been sporadically applied due to their rarity. To ascertain the presence of potential therapeutic targets, we analyzed by immunohistochemistry the expression of angiogenesis-related biomarkers in a large series of TET arranged in Tissue Micro Arrays (TMA). MATERIALS AND METHODS: We assessed by immunohistochemistry the expression of the possible molecular target of anti-angiogenic therapy, i.e. VEGFA, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, and PDGFRß, in a TMA series of 200 TET collected in the framework of a multi-institutional collaborative project for Rare Diseases. RESULTS: When compared to the low-risk tumors, high-risk TET (B2, B3, carcinomas) contained higher proportion of cancer cells expressing VEGFA, VEGFC and VEGFD (P<0.001, P<0.001, and P<0.001) growth factors, and their receptors VEGFR1 (P=0.002), VEGFR2 (P=0.013), and VEGFR3 (P=0.041). No differences were observed in terms of PDGFRß expression. CONCLUSIONS: According to our data, it is possible to hypothesize the existence of multiple paracrine and/or autocrine loops in TET, particularly in the high-risk ones, involved in TET growth and progression. Anti-angiogenic agents, directed to inhibit these loops, are therefore to be considered as potential tools in advanced TET therapy.

Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(-) cells and display an impaired capability to kill tumor cells.

BACKGROUND: Despite natural killer (NK) cells being originally identified and named because of their ability to kill tumor cells in vitro, only limited information is available on NK cells infiltrating malignant tumors, especially in humans. METHODS: NK cells infiltrating human nonsmall cell lung cancers (NSCLC) were analyzed with the aim of identifying their potential protective role in an antitumor immune response. Both relevant molecule expression and functions of NK cells infiltrating NSCLC were analyzed in comparison with autologous NK cells isolated from either peritumoral normal lung tissues or peripheral blood. RESULTS: The CD56 bright CD16(-) NK cell subset was consistently observed as being highly enriched in tumor infiltrate and displayed activation markers, including NKp44, CD69, and HLA-DR. Remarkably, the cytolytic potential of NK cells isolated from cancer tissues was lower than that of NK cells from peripheral blood or normal lung tissue, whereas no difference was observed regarding their capability of producing cytokines. With regard to their localization within tumor, NK cells were found in tumor stroma, whereas they were not in direct contact with cancer cells. CONCLUSIONS: For the first time NK cells infiltrating NSCLC have been characterized and it is shown that they are mainly capable of producing relevant cytokines rather than exerting direct cancer cell killing.