The identification of hub genes associated with pure ground glass nodules using weighted gene co-expression network analysis.

BACKGROUND: Whether there are invasive components in pure ground glass nodules(pGGNs) in the lungs is still a huge challenge to forecast. The objective of our study is to investigate and identify the potential biomarker genes for pure ground glass nodule(pGGN) based on the method of bioinformatics analysis. METHODS: To investigate differentially expressed genes (DEGs), firstly the data obtained from the gene expression omnibus (GEO) database was used.Next Weighted gene co-expression network analysis (WGCNA) investigate the co-expression network of DEGs. The black key module was chosen as the key one in correlation with pGGN. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were done. Then STRING was uesd to create a protein-protein interaction (PPI) network, and the chosen module genes were analyzed by Cytoscape software.In addition the polymerase chain reaction (PCR) was used to evaluate the value of these hub genes in pGGN patients' tumor tissues compared to controls. RESULTS: A total of 4475 DEGs were screened out from GSE193725, then 225 DEGs were identified in black key module, which were found to be enriched for various functions and pathways, such as extracellular exosome, vesicle, ribosome and so on. Among these DEGs, 6 overlapped hub genes with high degrees of stress method were selected. These hub genes include RPL4, RPL8, RPLP0, RPS16, RPS2 and CCT3.At last relative expression levels of CCT3 and RPL8 mRNA were both regulated in pGGN patients' tumor tissues compared to controls. CONCLUSIONS: To summarize, the determined DEGs, pathways, modules, and overlapped hub genes can throw light on the potential molecular mechanisms of pGGN.

Single-cell RNA sequencing reveals the multi-cellular ecosystem in different radiological components of pulmonary part-solid nodules.

BACKGROUND: Early-stage lung adenocarcinoma that radiologically manifests as part-solid nodules, consisting of both ground-glass and solid components, has distinctive growth patterns and prognosis. The characteristics of the tumour microenvironment and transcriptional features of the malignant cells of different radiological phenotypes remain poorly understood. METHODS: Twelve treatment-naive patients with radiological part-solid nodules were enrolled. After frozen pathology was confirmed as lung adenocarcinoma, two regions (ground-glass and solid) from each of the 12 part-solid nodules and 5 normal lung tissues from 5 of the12 patients were subjected to single-cell sequencing by 10x Genomics. We used Seurat v3.1.5 for data integration and analysis. RESULTS: We comprehensively dissected the multicellular ecosystem of the ground-glass and solid components of part-solid nodules at the single-cell resolution. In tumours, these components had comparable proportions of malignant cells. However, the angiogenesis, epithelial-to-mesenchymal transition, KRAS, p53, and cell-cycle signalling pathways were significantly up-regulated in malignant cells within solid components compared to those within ground-glass components. For the tumour microenvironment, the relative abundance of myeloid and NK cells tended to be higher in solid components than in ground-glass components. Slight subtype composition differences existed between the ground-glass and solid components. The T/NK cell subsets' cytotoxic function and the macrophages' pro-inflammation function were suppressed in solid components. Moreover, pericytes in solid components had a stronger communication related to angiogenesis promotion with endothelial cells and tumour cells. CONCLUSION: The cellular landscape of ground-glass components is significantly different from that of normal tissue and similar to that of solid components. However, transcriptional differences exist in the vital signalling pathways of malignant and immune cells within these components.

Intelligent immune clonal optimization algorithm for pulmonary nodule classification.

Computer-aided diagnosis (CAD) of pulmonary nodules is an effective approach for early detection of lung cancers, and pulmonary nodule classification is one of the key issues in the CAD system. However, CAD has the problems of low accuracy and high false-positive rate (FPR) on pulmonary nodule classification. To solve these problems, a novel method using intelligent immune clonal selection and classification algorithm is proposed and developed in this work. First, according to the mechanism and characteristics of chaotic motion with a logistic mapping, the proposed method utilizes the characteristics of chaotic motion and selects the control factor of the optimal chaotic state, to generate an initial population with randomness and ergodicity. The singleness problem of the initial population of the immune algorithm was solved by the proposed method. Second, considering on the characteristics of Gaussian mutation operator (GMO) with a small scale, and Cauchy mutation operator (CMO) with a big scale, an intelligent mutation strategy is developed, and a novel control factor of the mutation is designed. Therefore, a Gauss-Cauchy hybrid mutation operator is designed. Ultimately, in this study, the intelligent immune clonal optimization algorithm is proposed and developed for pulmonary nodule classification. To verify its accuracy, the proposed method was used to analyze 90 CT scans with 652 nodules. The experimental results revealed that the proposed method had an accuracy of 97.87% and produced 1.52 false positives per scan (FPs/scan), indicating that the proposed method has high accuracy and low FPR.

Recurrent YAP1-TFE3 Gene Fusions in Clear Cell Stromal Tumor of the Lung.

Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCST-L) is a recently described distinctive rare pulmonary neoplasm of unknown histogenesis and molecular pathogenesis. Only 7 cases have been reported in 2 recent studies, although additional cases might have been reported under the heading of extraneural pulmonary hemangioblastoma. We herein describe 4 CCST-L cases, 3 of them harboring a YAP1-TFE3 fusion. The fusion-positive tumors occurred in 3 women, aged 29, 56, and 69 years. All presented with solitary lung nodules measuring 2.3 to 9.5 cm. Histologically, all tumors showed similar features being composed of relatively uniform medium-sized epithelioid to ovoid cells with clear cytoplasm and small round monomorphic nuclei. Scattered larger cells with enlarged hyperchromatic nuclei and marked pleomorphism were noted in 2 cases. The tumors were associated with a hypervascularized stroma with variable but essentially subtle resemblance to capillary hemangioblastoma and perivascular epithelioid cell tumor (PEComa). Immunohistochemistry was negative for all lineage-specific markers. Targeted RNA sequencing showed a YAP1-TFE3 fusion in 3 of 4 cases. All 3 tumors showed homogeneous nuclear TFE3 immunoreactivity. Two patients were disease free at 36 and 12 months. The third patient had biopsy-proven synchronous renal and hepatic metastases, but extended follow-up is not available (recent case). The fourth case lacking the fusion affected a 66-year-old woman and showed subtle histologic differences from the fusion-positive cases, but had comparable TFE3 immunoreactivity. CCST-L represents a distinctive entity unrelated to hemangioblastoma and likely driven by recurrent YAP1-TFE3 fusions in most cases. The relationship of our cases to the recently reported "hemangioblastoma-like" CCST-L remains to be determined. Analysis of larger series is paramount to delineate the morphologic spectrum and biological behavior of this poorly characterized entity.

DNA methylation of PTGER4 in peripheral blood plasma helps to distinguish between lung cancer, benign pulmonary nodules and chronic obstructive pulmonary disease patients.

BACKGROUND/INTRODUCTION: In contrast to patients who present with advanced stage lung cancer and associated poor prognosis, patients with early-stage lung cancer may be candidates for curative treatments. The results of the NELSON lung cancer screening trial are expected to stimulate the development and implementation of a lung cancer screening strategy in most countries. Widespread use of chest computed tomography scans will also result in the detection of solitary pulmonary nodules. Because reliable biomarkers to distinguish between malignant and benign lesions are lacking, tissue-based histopathological diagnostics remain the gold standard. In this study, we aimed to establish a test to assess the predictive ability of DNA hypermethylation of SHOX2 and PTGER4 in plasma to discriminate between patients with 1.) lung cancer, 2.) benign lesions, and 3.) patients with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We retrospectively analysed SHOX2 and PTGER4 methylation in 121 prospectively collected plasma samples of patients with lung cancer (group 1A), benign lesions (group 1B), and COPD without nodules (group 2). RESULTS: PTGER4 DNA hypermethylation was more frequently observed in patients with lung cancer than in controls (p = 0.0004). Results remained significant after correction for tumour volume, smoking status, age, and eligibility for the NELSON trial. CONCLUSIONS: Detection of methylated PTGER4 in plasma DNA may serve as a biomarker to support clinical decision-making in patients with pulmonary lesions at lung cancer screening in high-risk populations. Further exploration in prospective studies is warranted.

Impact of the Percepta Genomic Classifier on Clinical Management Decisions in a Multicenter Prospective Study.

BACKGROUND: The Percepta genomic classifier has been clinically validated as a complement to bronchoscopy for lung nodule evaluation. RESEARCH QUESTION: The goal of this study was to examine the impact on clinical management decisions of the Percepta result in patients with low- and intermediate-risk lung nodules. STUDY DESIGN AND METHODS: A prospective "real world" registry was instituted across 35 US centers to observe physician management of pulmonary nodules following a nondiagnostic bronchoscopy. To assess the impact on management decisions of the Percepta genomic classifier, a subset of patients was analyzed who had an inconclusive bronchoscopy for a pulmonary nodule, a Percepta result, and an adjudicated lung diagnosis with at least 1 year of follow-up. In this cohort, change in the decision to pursue additional invasive procedures following Percepta results was assessed. RESULTS: A total of 283 patients met the study eligibility criteria. In patients with a low/intermediate risk of malignancy for whom the clinician had designated a plan for a subsequent invasive procedure, a negative Percepta result down-classified the risk of malignancy in 34.3% of cases. Of these down-classified patients, 73.9% had a change in their management plan from an invasive procedure to surveillance, and the majority avoided a procedure up to 12 months following the initial evaluation. In patients with confirmed lung cancers, the time to diagnosis was not significantly delayed when comparing Percepta down-classified patients vs patients who were not down-classified (P = .58). INTERPRETATION: The down-classification of nodule malignancy risk with the Percepta test decreased additional invasive procedures without a delay in time to diagnosis among those with lung cancer.

The combination of CTCs and CEA can help guide the management of patients with SPNs suspected of being lung cancer.

OBJECTIVE: Solitary pulmonary nodules (SPNs) is a common radiographic finding and require further evaluation because of the possibility of lung cancer. This study aimed to determine the sensitivity and specificity of circulating tumour cells (CTCs) as a marker for the diagnosis of SPNs and the integration of CTCs, carcinoembryonic antigen (CEA) and imaging findings to improve the sensitivity and specificity of diagnosis in patients with SPNs suspected of being lung cancer. METHOD: For the serum biomarker assay, the concentration of CEA was measured by an automated electrochemiluminescence analyzer. CTCs were collected from 6 ml of blood by the SE i-FISH method, which detects the gene copy number in eight chromosomes and the tumour-associated antigen CK18. RESULTS: With a threshold of 6 CTC units, the method showed a sensitivity of 67.1% and a specificity of 56.5% in the diagnosis of NSCLC, especially in the upper lobe, in which the diagnostic strength was the highest (P < 0.01). CTCs, CEA and nodule type had the highest diagnostic efficacy (area under the curve, 0.827; 95% confidence interval, 0.752-0.901) in patients with SPNs being suspected lung cancer. Combining CTCs (cut-off value 12 units) with CEA (1.78 ng/ml), the method showed a sensitivity of 77.8% and a specificity of 90% in the diagnosis of NSCLC, especially in the upper lobe, subsolid nodules and nodules ≥8 mm. CONCLUSIONS: Our results demonstrated that CTCs are feasible diagnostic biomarkers in patients with SPNs, especially in the upper lobe. Furthermore, CTCs combined with CEA showed higher diagnostic efficacy in the upper lobe, subsolid nodules and nodules ≥8 mm.

Diagnostic efficacy and molecular testing by combined fine-needle aspiration and core needle biopsy in patients with a lung nodule.

BACKGROUND: Combined image-guided fine-needle aspiration biopsy (FNA) and core needle biopsy (CNB) has become the standard of care for diagnosis and/or molecular testing for patients with a solitary lung nodule at our institution. Our purpose was to evaluate the efficacy of this practice. METHODS: We identified patients who underwent combined lung FNA/CNB during 2012 at our institution. A total of 667 patients who underwent 682 combined lung FNA/CNB procedures were included in the study, including 355 men and 312 women. Combined lung FNA/CNB procedures were performed by a radiologist. The adequacy of FNA specimens was assessed immediately by a cytopathologist. The FNA and CNB specimens were interpreted separately by a cytopathologist and a surgical pathologist, respectively. The diagnostic accuracy of the combined technique was determined. RESULTS: The rate of diagnostic consistency between FNA and CNB was 83.4%, and the rate of diagnostic accuracy for malignancy was 98.5% for combined FNA/CNB. Combined FNA/CNB showed a high diagnostic efficacy for malignancy (sensitivity, 97.6%; specificity, 100%). Combined FNA/CNB had a lower false-negative rate for malignancy (2.2%) than either FNA (7.2%) or CNB (6.2%) alone. FNA contributed to 10.3% of molecular analyses as a complementary tissue source. CONCLUSIONS: Combined lung FNA/CNB has high diagnostic efficacy for malignancy and a lower false-negative rate than either procedure alone. FNA was a valuable complement to CNB for molecular testing, potentially reducing patient inconvenience and morbidity associated with repeated lung needle biopsy.

Major challenges in accurate mutation detection of multifocal lung adenocarcinoma by next-generation sequencing.

Background: Many patients with advanced non-small cell lung cancer manifested with metastasis, and molecular heterogeneity may exhibit between primary and metastatic tumors. We sought to investigate the clinical detection strategy of primary and metastatic tumors in Chinese patients with NSCLC.Methods: Here, 77 paired tumors of Chinese patients with lung adenocarcinoma were analyzed, and 1836 mutation in hotspot regions of 22 genes were identified by next-generation sequencing. The expression of ALK in these paired tumors was also detected by immunohistochemistry.Results: The results showed that the concordance rate in multiple pulmonary nodules, primary-LN metastasis pairs and primary-distant metastasis pairs was 67.7%, 94.1% and 86.7%, respectively. In multiple pulmonary nodules, the concordance rate was 100% when the pathologic diagnosis was intrapulmonary metastasis, whereas the concordance rate was 23.1% when the pathologic diagnosis was multiple primary tumors. TP53 and CTNNB1 mutations were detected as the recurrent alterations in LN metastasis. Moreover, the concordance of ALK status was observed in these pairs.Conclusions: Our data suggested that hotspot mutations and ALK status in the primary-metastasis pairs had a high concordance in lung adenocarcinoma. Clinical detection of one lesion may be enough to identify the key alterations except that patients are diagnosed with multiple primary tumors or have disease progression after benefiting from target therapy.

Methylation of RUNX3 and RASSF1A and the risk of Malignancy in small solitary pulmonary nodules.

BACKGROUND: This study aimed to evaluate the methylation of RUNX3 and RASSF1A gene promoter regions as a marker to distinguish between benign and malignant of small solitary pulmonary nodule (SPN) ≤10 mm in size. MATERIALS AND METHODS: A total of 147 patients with pathologically confirmed SPNs were enrolled. DNA samples were extracted from biopsy tissues or serum. Methylation of RUNX3 and RASSF1A gene promoter regions was detected by the methylation-specific polymerase chain reaction. The expression of RUNX3 and RASSF1A in SPN tissues was detected by western blot. RESULTS: Of the 147 patients, 89 had benign SPNs and 58 had malignant SPNs. The rate of serum RUNX3 and RASSF1A gene methylation in malignant SPNs was significantly higher than that in benign SPNs (65.5% vs. 12.3%, and 67.2% vs. 10.1%, respectively; P < 0.05). The expression of RUNX3 and RASSF1A in malignant SPN tissues was lower than that in benign SPN tissues. The hypermethylation status of RUNX3 or RASSF1A genes was not significantly associated with age, gender, and smoking. CONCLUSIONS: The methylation level of the RUNX3 and RASSF1A gene promoter regions is a promising marker for assessing SPNs.

Effect of cyclical intermittent hypoxia on Ad5CMVCre induced solitary lung cancer progression and spontaneous metastases in the KrasG12D+; p53fl/fl; myristolated p110fl/fl ROSA-gfp mouse.

BACKGROUND: Epidemiological data suggests that obstructive sleep apnea (OSA) is associated with increased cancer incidence and mortality. We investigate the effects of cyclical intermittent hypoxia (CIH), akin to the underlying pathophysiology of OSA, on lung cancer progression and metastatic profile in a mouse model. METHODS: Intrathoracic injection of Ad5CMVCre virus into a genetically engineered mouse (GEM) KrasG12D+/-; p53fl/fl; myristolated-p110αfl/fl-ROSA-gfp was utilized to induce a solitary lung cancer. Male mice were then exposed to either CIH or Sham for 40-41 days until harvest. To monitor malignant progression, serial micro CT scans with respiratory gating (no contrast) was performed. To detect spontaneous metastases in distant organs, H&E and immunohistochemistry were performed. RESULTS: Eighty-eight percent of injected Ad5CMVCre virus was recovered from left lung tissue, indicating reliable and accurate injections. Serial micro CT demonstrated that CIH increases primary lung tumor volume progression compared to Sham on days 33 (p = 0.004) and 40 (p<0.001) post-injection. In addition, CIH increases variability in tumor volume on day 19 (p<0.0001), day 26 (p<0.0001), day 33 (p = 0.025) and day 40 (p = 0.004). Finally, metastases are frequently detected in heart, mediastinal lymph nodes, and right lung using H&E and immunohistochemistry. CONCLUSIONS: Using a GEM mouse model of metastatic lung cancer, we report that male mice with solitary lung cancer have accelerated malignant progression and increased variability in tumor growth when exposed to cyclical intermittent hypoxia. Our results indicate that cyclical intermittent hypoxia is a pathogenic factor in non-small cell lung cancer that promotes the more rapid growth of developing tumors.

Pulmonary Nodular Lymphoid Hyperplasia.

Pulmonary nodular lymphoid hyperplasia is an uncommon reactive lymphoproliferative disorder that presents as an asymptomatic lung mass. The histopathologic diagnosis of pulmonary nodular lymphoid hyperplasia may be challenging because of its morphologic overlap with other diseases, such as extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue and immunoglobulin G4-related sclerosing disease. Despite the similarities, there are distinctive morphologic and phenotypic features that allow for the correct diagnosis in the majority of cases. This review aims to discuss the clinicopathologic features of pulmonary nodular lymphoid hyperplasia and contrast them with its histopathologic mimickers.

Evaluation of ground glass nodules.

PURPOSE OF REVIEW: Ground glass nodules (GGNs) represent an indolent subset of lung nodules including preinvasive nonsmall-cell lung cancer associated with a favorable prognosis and low risk for progression. Increased performance of screening cat-scan (CT) for high-risk patients has identified an increasing number of GGNs. The management of these nodules is founded mostly on single institution data and currently no universally accepted recommendations help guide clinicians managing these patients. RECENT FINDINGS: The solid component within a GGN is the key determinant of prognosis and is best defined by evaluating nodule density on mediastinal windows of a chest CT. When a GGN is small (<3 cm), associated with minimal change in size (<25% growth per year), and there is no demonstration of a significant solid component on mediastinal windows (<2 mm in diameter), patients can be safely observed with serially imaging. These imaging features also help distinguish patients that may harbor early-stage lung cancers that benefit from local treatment options. SUMMARY: The majority of GGNs do not undergo significant progression during surveillance. Evidence of nodule progression on interval imaging may be a trigger for consideration of a local treatment option such as surgical resection. Large prospective studies are needed in the United States to validate the more robust data derived from Asian studies to help formulate formal recommendations for surveillance and treatment. Future improvements in imaging and the molecular characterization of these GGNs may further refine which patients are at risk for progression.

[The Clinical and Molecular Characteristics of Adenocarcinoma Presented 
by Multi-focal GGO].

Due to emphasis on early screening for lung cancer, the detection rate of multiple ground glass opacities (GGOs) on computed tomography (CT) image increases in recent years, and research on multifocal adenocarcinomas presented by GGOs has been thriving. It is more common in women and non-smokers and has excellent prognosis both in patients with natural history and after surgery. These clinical features suggest that it is likely to be a distinct disease entity. From the perspective of molecular genetics, lesions in the same individual are likely to have distinct clonal features. Therefore, genetic heterogeneity is the most prominent feature of multifocal pulmonary adenocarcinomas with GGOs. The genetic heterogeneity is expected to assist the diagnosis of multifocal pulmonary adenocarcinoma and intrapulmonary metastasis, and also suggests that genetic testing of the GGO lesions is of great therapeutic significance. Some GGO lesions may harvest the similar clonal feature, which provide new evidence for the theory of spread through air spaces (STAS).
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Identification of Proteomic Features To Distinguish Benign Pulmonary Nodules from Lung Adenocarcinoma.

We hypothesized that distinct protein expression features of benign and malignant pulmonary nodules may reveal novel candidate biomarkers for the early detection of lung cancer. We performed proteome profiling by liquid chromatography-tandem mass spectrometry to characterize 34 resected benign lung nodules, 24 untreated lung adenocarcinomas (ADCs), and biopsies of bronchial epithelium. Group comparisons identified 65 proteins that differentiate nodules from ADCs and normal bronchial epithelium and 66 proteins that differentiate ADCs from nodules and normal bronchial epithelium. We developed a multiplexed parallel reaction monitoring (PRM) assay to quantify a subset of 43 of these candidate biomarkers in an independent cohort of 20 benign nodules, 21 ADCs, and 20 normal bronchial biopsies. PRM analyses confirmed significant nodule-specific abundance of 10 proteins including ALOX5, ALOX5AP, CCL19, CILP1, COL5A2, ITGB2, ITGAX, PTPRE, S100A12, and SLC2A3 and significant ADC-specific abundance of CEACAM6, CRABP2, LAD1, PLOD2, and TMEM110-MUSTN1. Immunohistochemistry analyses for seven selected proteins performed on an independent set of tissue microarrays confirmed nodule-specific expression of ALOX5, ALOX5AP, ITGAX, and SLC2A3 and cancer-specific expression of CEACAM6. These studies illustrate the value of global and targeted proteomics in a systematic process to identify and qualify candidate biomarkers for noninvasive molecular diagnosis of lung cancer.

A classifier integrating plasma biomarkers and radiological characteristics for distinguishing malignant from benign pulmonary nodules.

Lung cancer is primarily caused by cigarette smoking and the leading cancer killer in the USA and across the world. Early detection of lung cancer by low-dose CT (LDCT) can reduce the mortality. However, LDCT dramatically increases the number of indeterminate pulmonary nodules (PNs), leading to overdiagnosis. Having a definitive preoperative diagnosis of malignant PNs is clinically important. Using microarray and droplet digital PCR to directly profile plasma miRNA expressions of 135 patients with PNs, we identified 11 plasma miRNAs that displayed a significant difference between patients with malignant versus benign PNs. Using multivariate logistic regression analysis of the molecular results and clinical/radiological characteristics, we developed an integrated classifier comprising two miRNA biomarkers and one radiological characteristic for distinguishing malignant from benign PNs. The classifier had 89.9% sensitivity and 90.9% specificity, being significantly higher compared with the biomarkers or clinical/radiological characteristics alone (all p < 0.05). The classifier was validated in two independent sets of patients. We have for the first time shown that the integration of plasma biomarkers and radiological characteristics could more accurately identify lung cancer among indeterminate PNs. Future use of the classifier could spare individuals with benign growths from the harmful diagnostic procedures, while allowing effective treatments to be immediately initiated for lung cancer, thereby reduces the mortality and cost. Nevertheless, further prospective validation of this classifier is warranted.

Air bronchogram: A potential indicator of epidermal growth factor receptor mutation in pulmonary subsolid nodules.

OBJECTIVES: Evaluation of pulmonary subsolid nodule is a longstanding clinical problem. We aimed to validate the computed tomography (CT) features correlating with pathological invasiveness and to explore any imaging findings associated with epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma. METHODS: A total of 204 patients with pathologically proven stage IA adenocarcinoma who had preoperative CT and data on EGFR status were enrolled in this retrospective study. Quantitative CT features including tumor size and solid volume proportion (SVP) were measured on multiplanar reconstructed images. Pathological analysis was stratified into adenocarcinoma in situ and minimally invasive adenocarcinoma (AIS/MIA), and invasive adenocarcinomas (IAs). RESULTS: There were 93 AIS/MIA and 111 IAs. EGFR mutation was detected in 109 (53.4%) cases. In radiopathological analysis, IAs were significantly in larger tumor size (15.8mm vs. 10.9mm), higher SVP (18.3% vs. 1.1%) and more likely to present air bronchogram, vascular invasion, lobulated/irregular shape, non-smooth margin and pleural tag than AIS/MIA. The multivariate logistic regression indicated that tumor size (OR=1.337) and SVP (OR=1.198) were significant differentiating factors of IAs from AIS/MIA. In radiogenomic analysis, EGFR status differed in tumor size, air bronchogram and margin. The multivariate logistic regression disclosed that the presence of an air bronchogram (OR=3.451) was significantly associated with EGFR mutation after adjustment for age, gender and smoking status. CONCLUSIONS: In subsolid nodules, tumor size and SVP were significant predictors of pathological invasiveness. In addition, the presence of air bronchogram was suggestive of activated EGFR mutation.

Dual-energy dynamic CT of lung adenocarcinoma: correlation of iodine uptake with tumor gene expression.

OBJECTIVES: To compare iodine content (IC) of solitary lung cancer using dynamic measurements of CT attenuation (Hounsfield Units, HU) and to correlate their quantitative CT data with expressions of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and hypoxia-inducible factor-1α (HIF-1α) using immunostaining methods. METHODS: This study included 18 patients with adenocarcinoma, who undergone dual energy dynamic multiphase CT to examine solitary lung nodules (6 part-solid and 12 solid nodules). Tumor size was 21.1 mm±8.1 (9-39mm) [Mean±SD (range)]. Contrast volume was determined by weight (2ml/kg). Contrast volume and injection rate were 110.5 ml±17.2 (80-144ml) and 1.84ml/s±0.30 (1.3-2.4ml/s), respectively. Enhancement values ([CT value at each delayed scan-CT value at unenhanced scan]) and net enhancement values ([peak CT value-CT value at unenhanced scan]) were calculated in HU from 65keV monochromatic image. IC at each delayed scan was measured in mg/cm(3) from the iodine-water material decomposition pair on the advantage workstation VolumeShare4. Immunostaining using VEGF, EGFR, and HIF-1α was performed by two pathologists, who evaluated the expression level of them subjectively. Statistical analyses were performed with rank correlation tests and regression analysis. RESULTS: IC at 2- and 3-minute delayed scan (x) and immunostaining score of HIF-1α (y) showed a significantly positive correlation (r=0.64 and 0.52, p=0.004 and 0.03): regression equation, y=1.34+0.58x and y=1.51+0.55x, respectively. CONCLUSIONS: Dual-energy dynamic multiphase CT can measure iodine content in lung adenocarcinoma. Iodine content at 2- and 3-minute delayed scan might correlate with the expression level of HIF-1α.

Pulmonary metastasis of a meningioma presenting as a solitary pulmonary nodule: 2 case reports.

Distant metastases of meningioma are rare, especially in grade 1 meningiomas. In a recent literature review, only 115 cases were found. In almost all published cases, the meningioma was treated several years before the metastasis was diagnosed. The lungs are the most frequent site of metastasis. We describe two patients treated for meningioma (one case grade 1, the other grade 3) who were referred to the Respiratory Oncology Unit because of the incidental finding of a pulmonary nodule on routine chest radiography. Both had undergone several neurosurgical procedures but the last operation was more than 7 years before in both cases. Positron emission tomography scan was suggestive of a malignant lung tumour. The lesions were surgically removed. Pathology confirmed meningioma in both cases with the same WHO grade, immunohistochemical and genetic profiles as the original meningioma. Both patients recovered well from thoracic surgery. The patient with grade 3 meningioma died three years later from intracranial recurrence. When a patient previously treated for meningioma develops a nodular lung lesion, metastasis of the meningioma should be in the differential diagnosis list. Because of the occurrence of distant metastasis even in grade I meningiomas, we suggest that the grading system should take into account genetic changes in the meningioma. Chromosome 1p and 14q losses possibly explain the aggressive behaviour of the grade 1 meningioma.

Serum phosphatidylethanolamine levels distinguish benign from malignant solitary pulmonary nodules and represent a potential diagnostic biomarker for lung cancer.

BACKGROUND: Recent computed tomography (CT) screening trials showed that it is effective for early detection of lung cancer, but were plagued by high false positive rates. Additional blood biomarker tests designed to complement CT screening and reduce false positive rates are highly desirable. OBJECTIVE: Identify blood-based metabolite biomarkers for diagnosing lung cancer. MEHTODS: Serum samples from subjects participating in a CT screening trial were analyzed using untargeted GC-TOFMS and HILIC-qTOFMS-based metabolomics. Samples were acquired prior to diagnosis (pre-diagnostic, n= 17), at-diagnosis (n= 25) and post-diagnosis (n= 19) of lung cancer and from subjects with benign nodules (n= 29). RESULTS: Univariate analysis identified 40, 102 and 30 features which were significantly different between subjects with malignant (pre-, at- and post-diagnosis) solitary pulmonary nodules (SPNs) and benign SPNs, respectively. Ten metabolites were consistently different between subjects presenting malignant (pre- and at-diagnosis) or benign SPNs. Three of these 10 metabolites were phosphatidylethanolamines (PE) suggesting alterations in lipid metabolism. Accuracies of 77%, 83% and 78% in the pre-diagnosis group and 69%, 71% and 67% in the at-diagnosis group were determined for PE(34:2), PE(36:2) and PE(38:4), respectively. CONCLUSIONS: This study demonstrates evidence of early metabolic alterations that can possibly distinguish malignant from benign SPNs. Further studies in larger pools of samples are warranted.