Low-dose computed tomography (LDCT) screening improves lung cancer prognosis but also results in diagnostic work-up and surgical treatment in many individuals without cancer. Therefore, we analysed the procedures that screening participants underwent to better understand the extent of overdiagnosis.Between 2009 and 2011, 8649 healthy volunteers aged 50-75 years with a 20 pack-year smoking history underwent LDCT screening, of whom individuals with detected lung nodules had 2 years control. Participants with a nodule >10 mm in diameter or with suspected tumour morphology underwent diagnostic work-up: 283 (6%)/4694 (54%) screened participants had detected lung nodules. One hundred and four individuals underwent surgery, 27 underwent oncological treatment and 152 without a cancer diagnosis underwent further follow-up with LDCT.In 75% of participants accepted for diagnostic work-up and 25% of surgical patients, the procedures were unnecessary. In 70 (24.7%) participants, a specific diagnosis was obtained mainly due to the low efficacy of fine needle aspiration biopsy [sensitivity, 65.2%; negative predictive value (NPV), 95.9%] and bronchofiberoscopy (sensitivity, 71.4%; NPV, 50%) caused by overinterpretation of LDCT [positive predictive value (PPV), 2%]. Of 104 (36.7%) surgical patients, 43 (41.4%) had a preoperative cancer diagnosis, and 61 (58.6%) underwent surgery without pathological examination. In the latter group, intervention was justified in 35 (57.3%) patients. Complications occurred in 49 (17.3%) participants subjected to diagnostic work-up. In surgical patients, 67 (64.4%) malignant and 37 (35.6%) benign lesions were resected. In the latter group, intervention was justified in only 11 (29.7%) patients. No patient died because of diagnostic or treatment procedures during the study. The complication rate was 14.5% in the malignant and 10.8% in the benign groups. A neoplasm was found in 94 screening participants, of whom 67 (71.3%) underwent surgery; the remaining 27 (28.7%) patients were not surgical candidates. Adenocarcinoma accounted for 49/67 (73%) patients who underwent surgery for non-small-cell lung cancer (NSCLC); 56/67 (84%) patients had stage I NSCLC, and 26/67 (38%) underwent video-assisted thoracoscopic surgery lobectomy.Futile diagnostic work-ups and operations must be reduced before LDCT screening can be broadly used. Stage I adenocarcinoma dominated in the NSCLC patients who underwent surgery.
Several panels of circulating miRNAs have been reported as potential biomarkers of early lung cancer, yet the overlap of components between different panels is limited and the universality of proposed biomarkers has been minimal across proposed panels. To assess the stability of the diagnostic potential of plasma miRNA signature of early lung cancer among different cohorts, a panel of 24 miRNAs tested in the frame of one lung cancer screening study (MOLTEST-2013, Poland) was validated with material collected in the frame of two other screening studies (MOLTEST-BIS, Poland and SMAC, Italy) using the same standardized analytical platform (the miRCURY LNA miRNA PCR Assay). The analysis of selected miRNAs revealed that two miRs associated with lung cancer development, miR-122 and miR-21, repetitively differentiated healthy participants of the screening and individuals with lung cancer. Additionally, miR-144 differentiated controls and cases specifically in sub-cohorts of adenocarcinomas. Other tested miRNAs did not overlap in the three cohorts. Moreover, classification models based on neither a single miRNA nor multicomponent miRNA panels (24-mer and 7-mer) showed sufficient classification performance required for a standalone diagnostic biomarker (AUC=0.75, AUC=0.70, and AUC=0.53 in MOLTEST-2013, SMAC, and MOLTEST-BIS, respectively, for 7-mer model). Furthermore, the performance of classification in the MOLTEST-BIS cohort with the lowest contribution of adenocarcinomas increased when only this cancer type was considered (AUC=0.60 for 7-mer). Several panels of circulating miRNAs have been reported as potential biomarkers of early lung cancer, yet the overlap of components between different panels is limited and the universality of proposed biomarkers has been minimal across proposed panels. To assess the stability of the diagnostic potential of plasma miRNA signature of early lung cancer among different cohorts, a panel of 24 miRNAs tested in the frame of one lung cancer screening study (MOLTEST-2013, Poland) was validated with material collected in the frame of two other screening studies (MOLTEST-BIS, Poland and SMAC, Italy) using the same standardized analytical platform (the miRCURY LNA miRNA PCR Assay). The analysis of selected miRNAs revealed that two miRs associated with lung cancer development, miR-122 and miR-21, repetitively differentiated healthy participants of the screening and individuals with lung cancer. Additionally, miR-144 differentiated controls and cases specifically in sub-cohorts of adenocarcinomas. Other tested miRNAs did not overlap in the three cohorts. Moreover, classification models based on neither a single miRNA nor multicomponent miRNA panels (24-mer and 7-mer) showed sufficient classification performance required for a standalone diagnostic biomarker (AUC=0.75, AUC=0.70, and AUC=0.53 in MOLTEST-2013, SMAC, and MOLTEST-BIS, respectively, for 7-mer model). Furthermore, the performance of classification in the MOLTEST-BIS cohort with the lowest contribution of adenocarcinomas increased when only this cancer type was considered (AUC=0.60 for 7-mer).
7612 Background: 5-year survival for surgically resected SCCL patients (p) is still limited. cDNA microarray studies have identified gene expression patterns that correlate with survival. We have examined the expression pattern of 29 genes selected by these studies to test their clinical prognostic value in early-stage SCCL. Methods: From 2000 to 2004, freshly frozen primary tumor specimens were obtained at the time of surgery from 66 Polish SCCL p. Sections were taken from blocks of tumor tissue for RNA extraction, and gene expression of the 29 genes was assessed by RT-QPCR (AB7900HT) using low density arrays (LDAs, Applied Biosystems). Expression values were dichotomized using the median value as the cut-off. Results: The univariate analysis showed 10 genes with prognostic value: PH4 (P=0.01); macrophage- colony stimulating factor (CSF1) (P=0.002); EGFR (P=0.05); KIAA0974 (P=0.02); ANLN (P=0.02); carbonic anhydrase IX (CA IX) (P=0.007); VEGFC (P=0.03); neurotrophic tyrosine receptor kinase 1 (P=0.04); fibronectin (P=0.002); insulin receptor (P=0.03). In the multivariate analysis of survival, CSF1, EGFR, CA IX and tumor size emerged as significant variables ( Table ). Conclusions: Tumor cells secrete CSF1, which attracts macrophages and induce them to express EGF, which in turn binds to EGFR in tumor cells. CA IX is regulated by hypoxia and plays a role in chemoresistance. Our findings highlight the relevance of tumor size and these markers in selecting p to receive adjuvant chemo- and targeted therapy. No significant financial relationships to disclose. [Table: see text]
<div>Abstract<p><b>Purpose:</b> Current staging methods are imprecise for predicting prognosis of early-stage non–small-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis.</p><p><b>Experimental Design:</b> We used whole-genome gene expression microarrays to analyze frozen tumor samples from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the samples were assigned as the training cohort with the remaining samples set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of individual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence.</p><p><b>Results:</b> We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (<i>P</i> < 0.001; <i>n</i> = 103) and in the independent validation set (<i>P</i> < 0.01; <i>n</i> = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response.</p><p><b>Conclusions:</b> Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.</p></div>
Purpose The purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non–small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis. Patients and Methods One hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181). Results IGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis. Conclusion IGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.
The aim of the present study is to evaluate the lung function before and after the lung decortication in patients with chronic pleural empyema (CPE).Twenty-six patients with diagnosis of CPE were evaluated in a prospective manner by lung perfusion scintigraphy, blood gas analysis and spirometry before and 35 weeks (+/-17) after the lung decortication.Preoperative scintigraphy showed reduction of lung perfusion on the affected side to 24.5% (+/-12.6%) in 11 right side empyemas (predicted value 55%) and to 18% (+/-8%) in 15 left side empyemas (predicted value 45%). The postoperative measurements showed improvement in perfusion to 45.2% (+/-7.7%) in patients with right side empyema and 34.1% (+/-8.5%) with the left side affection. The preoperative vital capacity (VC) was reduced to 62.3% (+/-13.8%) of the predicted value and forced expiratory volume in 1s (FEV1) to 50% (+/-15.5%) of the predicted value. Postoperatively, slight improvement was achieved to 79.8 % (+/-12.9%) for VC and 69.2% (+/-12.7%) for FEV1. Blood gas analysis showed decreased values in majority of the patients before operation and significant improvement in postoperative evaluation.Perfusion and spirometry improves significantly in patients with CPE after the lung decortication but function of the affected lung remains impaired. There was no influence of the age, gender, side of the disease, bacteriology or duration of the empyema before operation on lung function.
11556 Background: Therapies aimed at activation of T and NK cells are developed to expand NSCLC treatments options. It is conceivable that markers of ‘immune ignorant’, ‘immune excluding’ or ‘inflamed’ tumor phenotypes could be prognostic or predictive of benefit from specific immune-targeting therapies. Aim: To assess the prognostic value of expression of T and NK cells mRNA markers and immune-related genes in early stage NSCLC. Methods: qRT-PCR was used to assess 48 mRNAs levels in frozen cancer tissue sections and matched normal lung parenchyma from 56 surgically treated stage I-IIIA NSCLC patients. The mRNA expression (normalized vs. 4 reference genes) was compared between the groups that did (44%) or did not relapse, as well as clinicopathological features (33% never-smokers, 75% lung adenocarcinoma). Results: Low expression of FAS-L (p.adj. = 0.048) , TIGIT and LAG3 was correlated with shorter distant metastasis free survival (DMFS) (p < 0.04). Expression of PD-1 (p = 0.024) and CTLA4 (p = 0.04) was significantly lower in relapsed vs. non-relapsed NSCLCs, whereas there was no difference for PDL-1 and PDL-2. Expression of NK activation markers: NCR3 and NCR1, but not NCR3-ligand 1 was significantly lower in relapsed vs. not relapsed NSCLCs. Other NK cell markers: CD96 and NKG2D were expressed at lower levels (p = 0.02) in relapsed vs. not relapsed NSCLCs, whereas there was no difference for NKG2C and NKG2A. Expression of CXCR3 was lower in relapsed NSCLCs (p = 0.03), however, the expression of its ligands (chemoattractants for lymphocytes) - CXCL9, CXCL10 or CXCL11 or endothelin receptor type B was not different according to metastatic status. GITR and FOXP3 expression was significantly higher in cancers vs. normal lung parenchyma (p.adj. < 0.003). There were no differences in expression according to gender, smoking or NSCLC histological types. Conclusions: Non-inflamed NSCLC phenotype is associated with higher risk of dissemination after primary resection. Neoplastic tissue is characterized by higher level of immune tolerance in comparison to normal lung tissue.
