Diagnostic value of conventional tumor markers in young patients with pulmonary nodules.

BACKGROUND: Lung cancer is one of the most common malignancies, and there is a trend of increasing incidence in young patients. The preoperative diagnosis of pulmonary nodules is mainly based on the combination of imaging and tumor markers. There is no relevant report on the diagnostic value of tumor markers in young pulmonary nodules. Our study was designed to explore the value of five tumor markers in young patients with pulmonary nodules. METHODS: We reviewed the medical records of 390 young patients (age ≤45 years) with pulmonary nodules treated at two separate centers from January 1, 2015, to January 1, 2021. Malignant pulmonary nodules were confirmed in 318 patients, and the other 72 patients were diagnosed with benign pulmonary nodules. The gold standard for diagnosis of pulmonary nodules was surgical biopsy. The conventional serum biomarkers included cytokeratin 19 (CYFRA21-1), pro-gastrin-releasing-peptide (ProGRP), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and squamous cell carcinoma-associated antigen (SCCA). The diagnostic values of five tumor markers were analyzed by receiver operating characteristic (ROC) curves. RESULTS: There were no significant differences in the expression of five tumor markers between the groups (p > 0.05). Single tumor marker (CYFRA21-1, ProGRP, CEA, NSE, and SCCA) showed a limited value in the diagnosis of malignant pulmonary nodules, with the AUC of 0.506, 0.503 0.532, 0.548, and 0.562, respectively. The AUC of the combined examination was only 0.502~0.596, which did not improve the diagnostic value. CONCLUSIONS: Five conventional tumor markers had a limited diagnostic value in young patients with pulmonary nodules.

[Value of Combined Detection of Cytokines and Tumor Markers in the 
Differential Diagnosis of Benign and Malignant Solitary Pulmonary Nodules].

BACKGROUND: Solitary pulmonary nodule has received increasing attention in recent years. A couple of lung nodules have been recognized as primary malignant tumors, which leads to an urgent need in enhancing the diagnosis of benign/malignant lung nodules at clinical settings. This study aims to explore the value of the combined detection of cytokines and tumor markers in differencing benign and malignant solitary pulmonary nodules in diagnose. METHODS: With 81 solitary pulmonary nodules cases with a clear diagnosis, the general clinical data, nodule imaging features, pathological diagnosis data, serological index cytokine series and tumor marker expression levels were collected in groups. Both single factor and multi-factors analysis were conducted to screen out the serum influence indexes that can predict the malignant probability of lung nodules, and mean while binary logistic regression analysis was used to construct joint indexes; After receiver operating characteristic curve (ROC) was drawn, the area under the curve and the corresponding sensitivity, specificity and positive of each index predicted value, negative predicted value and accuracy could be calculated with a view to determine the statistical significance of area under the curve (AUC). RESULTS: There are differences in the distribution of malignant solitary pulmonary nodules at different locations, with the highest proportion of the right upper lobe (40.4%). The serum levels of carcinoembryonic antigen (CEA), cytokeratin 19 fragment 21-1 (CYFRA21-1), interleukin-6 (IL-6), interleukin-8 (IL-8) in the malignant nodule group were higher than those in the benign nodule group. Logistic regression analysis suggests that CEA, IL-6 and IL-8 are independent risk factors for predicting malignant nodules. ROC curve analysis shows that the areas under the curve of the individual indicators CEA, IL-6 and IL-8 are 0.642, 0.684 and 0.749. The comparison result of the test efficiency of the area under the curve suggests that CEA+IL-6+IL-8 has a larger area under the curve and higher detection efficiency. CONCLUSIONS: CEA, IL-6 and IL-8 are independent risk factors for malignant solitary pulmonary nodules. The combined detection of cytokines and tumor markers has played a role in the differential diagnosis of benign and malignant lung nodules. The diagnostic value of the combined detection of CEA+IL-6+IL-8 is the highest.

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.

A model based on the quantification of complement C4c, CYFRA 21-1 and CRP exhibits high specificity for the early diagnosis of lung cancer.

Lung cancer screening detects early-stage cancers, but also a large number of benign nodules. Molecular markers can help in the lung cancer screening process by refining inclusion criteria or guiding the management of indeterminate pulmonary nodules. In this study, we developed a diagnostic model based on the quantification in plasma of complement-derived fragment C4c, cytokeratin fragment 21-1 (CYFRA 21-1) and C-reactive protein (CRP). The model was first validated in two independent cohorts, and showed a good diagnostic performance across a range of lung tumor types, emphasizing its high specificity and positive predictive value. We next tested its utility in two clinically relevant contexts: assessment of lung cancer risk and nodule malignancy. The scores derived from the model were associated with a significantly higher risk of having lung cancer in asymptomatic individuals enrolled in a computed tomography (CT)-screening program (OR = 1.89; 95% CI = 1.20-2.97). Our model also served to discriminate between benign and malignant pulmonary nodules (AUC: 0.86; 95% CI = 0.80-0.92) with very good specificity (92%). Moreover, the model performed better in combination with clinical factors, and may be used to reclassify patients with intermediate-risk indeterminate pulmonary nodules into patients who require a more aggressive work-up. In conclusion, we propose a new diagnostic biomarker panel that may dictate which incidental or screening-detected pulmonary nodules require a more active work-up.

Establishment and validation of a prediction model for the probability of malignancy in solid solitary pulmonary nodules in northwest China.

BACKGROUND AND OBJECTIVES: To construct a prediction model of solitary pulmonary nodules (SPNs), to predict the possibility of malignant SPNs in patients aged 15-85 years in northwest China for clinical diagnostic and therapeutic decision-making. METHODS: The features of SPNs were assessed by multivariate logistic regression, followed by visualization using a nomogram. Hosmer lemeshow was applied to evaluate the fitting degree of the model. The area under the receiver operating characteristic (ROC) curve was identified to determine the discriminative ability of the model. RESULTS: Lobulation, spiculation, pleural-tag, carcinoembryonic antigen, neuron-specific enolase, and total serum protein were independent predictors of malignant pulmonary nodules (p < .05). Lobulation (100 points) scored the highest in the nomogram, and the Hosmer-Lemeshow goodness-of-fit statistic was 0.805 (p > .05). The area under curve (AUC) of the modeling and validation groups using logistic regression were 0.859 (95% CI, 0.805-0.903) and 0.823 (95% CI, 0.738-0.890), respectively. Moreover, the AUC of our model was higher than that of the Mayo model, VA model, and Peking University (AUC 0.823 vs. 0.655 vs. 0.603 vs. 0.521). CONCLUSION: Our prediction model is more suitable for predicting the possibility of malignant SPNs in northwest China, and can be calculated using a nomogram to determine further treatments.

Value of folate receptor-positive circulating tumour cells in the clinical management of indeterminate lung nodules: A non-invasive biomarker for predicting malignancy and tumour invasiveness.

BACKGROUND: Non-invasive lung adenocarcinoma could benefit from limited resection, nonetheless, there is a lack of method to determine preoperative tumour invasiveness. We aimed to investigate whether folate receptor-positive circulating tumour cells (FR+-CTCs) in combination with maximum tumour diameter (MTD) determines, before surgery, the invasiveness of small-sized, indeterminate solitary pulmonary nodules (SPNs). METHODS: A total of 382 patients with suspicious lung adenocarcinoma on computed tomography who were expected to undergo lung resection were enrolled in this study at three participating institutes and randomly assigned into training and validation cohorts. Before surgery, 3 mL peripheral blood was collected from all participants. FR+-CTCs were analyzed using immunomagnetic leukocyte depletion and quantitated by ligand-targeted PCR method. After surgery, the resected tissues were diagnosed by pathologists according to IASLC/ATS/ERS classification. FINDINGS: FR+-CTC levels in the peripheral blood can differentiate benign from malignant nodules with a sensitivity of 78·6%-82·7% and a specificity of 68·8%-78·4%. Both FR+-CTC and MTD are independent predictive indices of invasive tumours for lung adenocarcinoma ≤2 cm based on multivariate analyses. Further, FR+-CTC count in combination with MTD can differentiate non-invasive cancers from invasive cancers with a sensitivity of 63·6%-81·8% and a specificity of 71·4%-89·7%. INTERPRETATION: Detection of FR+-CTC is a reliable method to differentiate malignancy of indeterminate SPNs. Combining of FR+-CTC count and MTD could possibly enhance preoperative determination of the invasiveness of lung nodules and guide surgeons to select limited lung resection and avoid overtreatment for patients with non-invasive lesions. FUND: None.

Folate-receptor-positive circulating tumor cells as an efficacious biomarker for the diagnosis of small pulmonary nodules.

OBJECTIVE: The objective of this study is to investigate the clinical significance of folate-receptor-positive circulating tumor cells (FR+CTC) for the diagnosis of lung cancer, especially in early-stage patients. MATERIALS AND METHODS: A total of 72 lung cancer patients, including 31 with stage I diseases and two with stage 0 diseases, were enrolled in this study. Twenty-four patients with benign lung diseases and two healthy volunteers served as the control group. Three milliliters of peripheral blood were collected from each participant for FR+CTC analysis on enrollment. FR+CTC enumeration was performed using immunomagnetic leukocyte depletion and ligand-targeted polymerase chain reaction techniques. RESULTS: The study results revealed that using a cutoff value of 8.7 CTC Units/3 mL, the sensitivity, and specificity of FR+CTC for diagnosis of lung cancer were 81.94% and 73.08%, respectively. Such high sensitivity (74.19%) and specificity (73.08%) persisted even if only stage I lung cancer patients were retained in the analysis. In receiver operating characteristic analysis, the performance of FR+CTC (area under the curve = 0.8153) was superior to other clinical biomarkers such as carcinoembryonic antigen, neuron-specific enolase, and cytokeratin 19 fragments. In a subgroup analysis, patients with nodule size of >3 cm showed an improved sensitivity (88.46%); although, the specificity appeared to decrease (40%). All five patients with benign diseases in this subgroup had inflammatory diseases, indicating that large inflammatory nodules may also release FR -expressing cells into the circulatory system. CONCLUSION: FR+CTC is a reliable biomarker for the early diagnosis of small-sized lung cancer. Further study with larger sample size is required to assess the diagnostic efficiency of FR+CTC in patients with large nodule sizes.

Identification of preoperative prediction factors of tumor subtypes for patients with solitary ground-glass opacity pulmonary nodules.

BACKGROUND: Recent wide spread use of low-dose helical computed tomography for the screening of lung cancer have led to an increase in the detection rate of very faint and smaller lesions known as ground-glass opacity nodules. The purpose of this study was to investigate the clinical factors of lung cancer patients with solitary ground-glass opacity pulmonary nodules on computed tomography. METHODS: A total of 423 resected solitary ground-glass opacity nodules were retrospectively evaluated. We analyzed the clinical, imaging and pathological data and investigated the clinical differences in patient with adenocarcinoma in situ / minimally invasive adenocarcinoma and those with invasive adenocarcinoma. RESULTS: Three hundred and ninety-three adenocarcinomas (92.9%) and 30 benign nodules were diagnosed. Age, the history of family cancer, serum carcinoembryonic antigen level, tumor size, ground-glass opacity types, and bubble-like sign in chest CT differed significantly between adenocarcinoma in situ / minimally invasive adenocarcinoma and invasive adenocarcinoma (p:0.008, 0.046, 0.000, 0.000, 0.000 and 0.001). Receiver operating characteristic curves and univariate analysis revealed that patients with more than 58.5 years, a serum carcinoembryonic antigen level > 1.970 µg/L, a tumor size> 13.50 mm, mixed ground-glass opacity nodules and a bubble-like sign were more likely to be diagnosed as invasive adenocarcinoma. The combination of five factors above had an area under the curve of 0.91, with a sensitivity of 82% and a specificity of 87%. CONCLUSION: The five-factor combination helps us to distinguish adenocarcinoma in situ / minimally invasive adenocarcinoma from invasive adenocarcinoma and to perform appropriate surgery for solitory ground-glass opacity nodules.

Combination diagnosis of multi-slice spiral computed tomography and secretary phospholipase A2-IIa for solitary pulmonary nodules.

INTRODUCTION: This study was aimed to compare the diagnostic value of multi-slice spiral computed tomography (CT) and secretary phospholipase A2-IIa (sPLA2-IIa) in differentiating between malignant and benign solitary pulmonary nodules (SPNs). METHODS: A total of 223 patients with SPNs (91 patients with malignant SPNs and 132 patients with benign SPNs) were included from Weihai Central Hospital during October 2014 to December 2016. SPN diagnosis was confirmed in all patients using needle biopsy, surgery and bronchoscopy. The patients were managed with dynamic multi-slice CT scans, and their sPLA2-IIa levels were also detected. By selecting the area of interest of focus, the perfusion parameters of multi-slice CT targeting the focus were obtained. RESULTS: The levels of MTT, PS, BV, BF and sPLA2-IIa significantly increased with increasing severity of SPNs (P<.05). Notably, BV (area under the ROC curve [AUC]=0.915; 95%CI: 0.88-0.95; sensitivity=91.21%; specificity=78.79%) showed a higher potential to discriminate patients with malignant SPNs from those with benign SPNs than did BF (AUC=0.712; 95%CI: 0.65-0.78; sensitivity=72.50%; specificity=59.10%), PS (AUC=0.772; 95%CI: 0.71-0.84; sensitivity=65.93%; specificity=82.58%) and MTT (AUC=0.600; 95%CI: 0.52-0.68; sensitivity=52.75%; specificity=78.03%). Finally, the combined diagnostic value of BV and sPLA2-IIa was quite ideal (AUC=0.947; 95%CI: 0.92-0.97; sensitivity=85.70%; specificity=92.70%) for malignant and benign SPNs. CONCLUSIONS: The combined diagnostic value of BV and sPLA2-IIa appeared as a desirable detection method for malignant and benign SPNs.

The value of macrophage inhibitory cytokine-1 level in differentiating benign from malignant solitary pulmonary nodules.

INTRODUCTION: Macrophage inhibitory cytokine-1 (MIC-1), a transforming growth factor-ß superfamily cytokine, is involved in tumor pathogenesis, and its measurement can be used as a clinical tool for the diagnosis of a wide range of cancers. OBJECTIVES: The aim of this study was to explore the diagnostic value of serum MIC-1 in patients with solitary pulmonary nodules (SPNs). METHODS: Serum specimens from 158 malignant SPN patients, 110 benign SPN patients, along with 120 healthy volunteers. The levels of serum MIC-1 were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: Serum levels of MIC-1 in malignant SPN patients were significantly higher than those in benign SPN patients (P < .01), or those in healthy volunteers (P < .01). With a cutoff of 685.8 pg/ml, the sensitivity and specificity of MIC-1 in differentiating between malignant SPN patients and benign SPN patients, and between malignant SPN patients and healthy volunteers was, 56.3% and 92.7%, and 65.8% and 96.7%, respectively. An area under the curve (AUC) for malignant SPN resulting from MIC-1, which was significantly better than any other tumor markers tested including carbohydrate antigens 12-5 (CA125), and carcinoembryonic antigen (CEA). CONCLUSIONS: In conclusion, measurement of serum MIC-1 levels could be considered as a diagnostic biomarker for malignant SPN patients.

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.

Combining serum miRNAs, CEA, and CYFRA21-1 with imaging and clinical features to distinguish benign and malignant pulmonary nodules: a pilot study : Xianfeng Li et al.: Combining biomarker, imaging, and clinical features to distinguish pulmonary nodules.

BACKGROUND: Our study was designed to improve the accuracy of determining whether pulmonary nodules are benign or malignant. METHODS: We evaluated the clinical and imaging features and serum markers: neuron specific enolase (NSE), carcino-embryonic antigen (CEA), cytokeratin fragment antigen 21-1 (CYFRA 21-1), miRNA-21-5p, and miR-574-5pof in 39 patients with pathology information. Factors that differed significantly between those with benign versus malignant pulmonary nodules were used to establish a prediction model for identifying malignant nodules. RESULTS: The studied nodules were 51.3% malignant and 48.7% benign. Age, smoking status, nodule diameter, history of emphysema, vascular sign, burr sign, CYFRA21-1, CEA, miRNA-21-5p, and miRNA-574-5p differed significantly between the benign and malignant nodule groups. Serum levels of CYRFA21-1 and CEA could be used to distinguish between malignant and benign nodules with a positive predictive value (PPV) of 80.0%, a negative predictive value (NPV) of 84.2%, and an area under the receiver operating characteristics curve (AUC) of 0.863. Using the serum levels of miRNA-21-5p and miRNA-574-5p, the PPV was 55%, the NPV was 84.2%, and the AUC was 0.797. When all four serum markers were combined, the PPV was 80%, the NPV was 89.5%, and the AUC was 0.921. We established a prediction model for malignant nodules, including clinical features, imaging features, and serum markers. In cross-validation, the ratio of discriminant conformance was 95%. CONCLUSIONS: Serum levels of miRNA-21-5p and miRNA-574-5p are significantly higher in patients with malignant nodules than in patients with benign nodules and are potential serum biomarkers. Our prediction model could improve malignant nodule diagnosis.

Autoantibody Signature Enhances the Positive Predictive Power of Computed Tomography and Nodule-Based Risk Models for Detection of Lung Cancer.

INTRODUCTION: The incidence of pulmonary nodules is increasing with the movement toward screening for lung cancer by low-dose computed tomography. Given the large number of benign nodules detected by computed tomography, an adjunctive test capable of distinguishing malignant from benign nodules would benefit practitioners. The ability of the EarlyCDT-Lung blood test (Oncimmune Ltd., Nottingham, United Kingdom) to make this distinction by measuring autoantibodies to seven tumor-associated antigens was evaluated in a prospective registry. METHODS: Of the members of a cohort of 1987 individuals with Health Insurance Portability and Accountability Act authorization, those with pulmonary nodules detected, imaging, and pathology reports were reviewed. All patients for whom a nodule was identified within 6 months of testing by EarlyCDT-Lung were included. The additivity of the test to nodule size and nodule-based risk models was explored. RESULTS: A total of 451 patients (32%) had at least one nodule, leading to 296 eligible patients after exclusions, with a lung cancer prevalence of 25%. In 4- to 20-mm nodules, a positive test result represented a greater than twofold increased relative risk for development of lung cancer as compared with a negative test result. Also, when the "both-positive rule" for combining binary tests was used, adding EarlyCDT-Lung to risk models improved diagnostic performance with high specificity (>92%) and positive predictive value (>70%). CONCLUSIONS: A positive autoantibody test result reflects a significant increased risk for malignancy in lung nodules 4 to 20 mm in largest diameter. These data confirm that EarlyCDT-Lung may add value to the armamentarium of the practitioner in assessing the risk for malignancy in indeterminate pulmonary nodules.

Evaluation of a Flexible NOTA-RGD Kit Solution Using Gallium-68 from Different 68Ge/68Ga-Generators: Pharmacokinetics and Biodistribution in Nonhuman Primates and Demonstration of Solitary Pulmonary Nodule Imaging in Humans.

PURPOSE: Radiopharmaceuticals containing the motive tripeptide arginyl-glycyl-asparatic acid (RGD) are known to target ανß3 integrins during tumor angiogenesis. A more generic kit radiolabeling procedure accommodating Ga-68 from different generators was developed for NOTA-RGD and evaluated for its versatile use and safety in subsequent in vivo applications. The [68Ga]NOTA-RGD kit was further verified for its expected biodistribution and pharmacokinetics in nonhuman primates and its clinical sensitivity to detect solitary pulmonary nodules (SPN) in cancer patients. PROCEDURES: Single vial kits containing 28-56 nmol of NOTA-cyclo-Arg-Gly-Asp-d-Tyr-Lys (NOTA-RGD) and sodium acetate trihydrate buffer were formulated. Versatility of the NOTA-RGD radiolabeling performance and adaption to a TiO2- and a SnO2-based generator type, characterization and long-term storage stability of the kits were carried out. The blood clearance and urine recovery kinetics as well as the image-guided biodistribution of [68Ga]NOTA-RGD was studied in a vervet monkey model. [68Ga]NOTA-RGD kits were further tested clinically to target solitary pulmonary nodules. RESULTS: The kits could be successfully formulated warranting integrity over 3-4 months with a good [68Ga]NOTA-RGD radiolabeling performance (radiochemical purity >95 %, decay corrected yield 76-94 %, specific activity of 8.8-37.9 GBq/µmol) The kits met all quality requirements to be further tested in vivo. [68Ga]NOTA-RGD cleared rapidly from blood and was majorly excreted via the renal route. The liver, spleen, heart and intestines showed initial uptake with steadily declining tissue activity concentration over time. In addition, the [68Ga]NOTA-RGD kit allowed for delineation of SPN from non-malignant lung tissue in humans. CONCLUSIONS: A more versatile radiolabeling procedure using kit-formulated NOTA-RGD and different generator types was achieved. The uncompromised in vivo behavior and efficient targeting of SPN warrants further investigations on the clinical relevance of [68Ga]NOTA-RGD derivatives to implement initial guidelines and management of patients, with regard to integrin targeted imaging.

Serum Angiopoietin-2 as a Clinical Marker for Lung Cancer in Patients with Solitary Pulmonary Nodules.

To evaluate the clinical significance of angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) in lung cancer patients with solitary pulmonary nodule (SPN). The study enrolled 128 patients with malignant SPN, 60 patients with benign SPN, along with 40 healthy volunteers. Serum concentrations of Ang-2 and VEGF were measured by ELISA. Serum Ang-2 and VEGF levels in patients with malignant SPN were significantly higher than those in patients with benign SPN (p<0.01), and those in healthy volunteers (p<0.05). With a cutoff of 1504.8 pg/mL, the sensitivity and specificity of Ang-2 in differentiating between patients with malignant SPN and patients with benign SPN, and between patients with malignant SPN and healthy volunteers was 69.5 and 92.5%, and 80.5 and 97.5%, respectively. Additionally, higher levels of Ang-2 were associated with higher tumor stage (p<0.05). The levels of Ang-2 correlated with the VEGF level (p<0.01). In conclusion, measurement of serum Ang-2 might be a useful diagnostic marker for SPN patients.

Clinical Utility of a Plasma Protein Classifier for Indeterminate Lung Nodules.

Evaluation of indeterminate pulmonary nodules is a complex challenge. Most are benign but frequently undergo invasive and costly procedures to rule out malignancy. A plasma protein classifier was developed that identifies likely benign nodules that can be triaged to CT surveillance to avoid unnecessary invasive procedures. The clinical utility of this classifier was assessed in a prospective-retrospective analysis of a study enrolling 475 patients with nodules 8-30 mm in diameter who had an invasive procedure to confirm diagnosis at 12 sites. Using this classifier, 32.0 % (CI 19.5-46.7) of surgeries and 31.8 % (CI 20.9-44.4) of invasive procedures (biopsy and/or surgery) on benign nodules could have been avoided. Patients with malignancy triaged to CT surveillance by the classifier would have been 24.0 % (CI 19.2-29.4). This rate is similar to that described in clinical practices (24.5 % CI 16.2-34.4). This study demonstrates the clinical utility of a non-invasive blood test for pulmonary nodules.

Angiogenesis Biomarkers May Be Useful in the Management of Patients With Indeterminate Pulmonary Nodules.

BACKGROUND: Low-dose computed tomography (CT) lung cancer screening is known to have a high false positive rate. This study aims to survey biomarkers of angiogenesis for those capable of assigning clinical significance to indeterminate pulmonary nodules detected through CT imaging studies. METHODS: An institutional database and specimen repository was used to identify 193 patients with stage I non-small cell lung cancer (T1N0M0) and 110 patients with benign solitary pulmonary nodules detected by CT imaging studies. All specimens were evaluated in a blinded manner for 17 biomarkers of angiogenesis using multiplex immunoassays. Biomarker performance was calculated through the Mann-Whitney rank sum U test and a receiver operator characteristic analysis. These data were used to refine our previously reported multi-analyte classification panel, which was then externally validated against an independent patient cohort (n = 80). RESULTS: A total of 303 patients were screened for 17 biomarkers of angiogenesis. Median nodule size was 1.2 cm for benign cases and 1.8 cm for non-small cell lung cancer, whereas median smoking histories were 25 and 40 pack-years, respectively. Differences in serum concentrations of heparin-binding epidermal growth factor (HB-EGF), epidermal growth factor (EGF), vascular (V)EGF-A, VEGF-C, and VEGF-D were strongly significant (p ≤ 0.001) while follistatin, placental growth factor (PLGF), and bone morphogenic protein (BMP)-9 were significant (p ≤ 0.05) between patients with benign and malignant nodules. Our previously reported multi-analyte classification panel was refined to include interleukin (IL)-6, IL-10, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF)-α, insulin-like growth factor binding protein (IGFBP)-5, IGFBP-4, IGF-2, stromal cell-derived factor (SDF)-1(α+ß), HB-EGF, and HGF resulting in improved accuracy and a validated negative predictive value of 96.4%. CONCLUSIONS: Angiogenesis biomarkers may be useful in discriminating stage I NSCLC from benign pulmonary nodules.

Significance of plasma hepatocyte growth factor in diagnosis of benign and malignant solitary pulmonary nodules.

PURPOSE: We aimed to figure out the difference of serum hepatocyte growth factor (S-HGF) level between benign and malignant solitary pulmonary nodules (SPNs) patients. METHODS: The study comprised 42 serum samples from SPNs patients and 10 serum samples of healthy donors. The HGF level was measured by the commercially enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: By statistical analysis, the S-HGF levels of the malignant SPNs patients were significantly higher than that of control group (P < 0.05). Moreover, the levels of S-HGF in malignant group were also significantly higher than that in benign group (P < 0.05), while there was no significant difference between the benign and control group (P > 0.05). The levels of S-HGF were also shown no statistically significant difference (P > 0.05) in different pathologic types of lung cancer patients. In addition, the incidence of malignant SPNs increased when the S-HGF level ≥ 250 pg/ml. CONCLUSION: The detection of S-HGF level may be a new detection method used for the rapid diagnosis of benign and malignant SPNs.

Analysis of the discriminative methods for diagnosis of benign and malignant solitary pulmonary nodules based on serum markers.

BACKGROUND: Screening indexes of tumor serum markers for benign and malignant solitary pulmonary nodules (SPNs) were analyzed to find the optimum method for diagnosis. METHODS: Enzyme-linked immunosorbent assays, an automatic immune analyzer and radioimmunoassay methods were used to examine the levels of 8 serum markers in 164 SPN patients, and the sensitivity for differential diagnosis of malignant or benign SPN was compared for detection using a single plasma marker or a combination of markers. The results for serological indicators that closely relate to benign and malignant SPNs were screened using the Fisher discriminant analysis and a non-conditional logistic regression analysis method, respectively. The results were then verified by the k-means clustering analysis method. RESULTS: The sensitivity when using a combination of serum markers to detect SPN was higher than that using a single marker. By Fisher discriminant analysis, cytokeratin 19 fragments (CYFRA21-1), carbohydrate antigen 125 (CA125), squamous cell carcinoma antigen (SCC) and breast cancer antigen (CA153), which relate to the benign and malignant SPNs, were screened. Through non-conditional logistic regression analysis, CYFRA21-1, SCC and CA153 were obtained. Using the k-means clustering analysis, the cophenetic correlation coefficient (0.940) obtained by the Fisher discriminant analysis was higher than that obtained with logistic regression analysis (0.875). CONCLUSION: This study indicated that the Fisher discriminant analysis functioned better in screening out serum markers to recognize the benign and malignant SPN. The combined detection of CYFRA21-1, CA125, SCC and CA153 is an effective way to distinguish benign and malignant SPN, and will find an important clinical application in the early diagnosis of SPN.

Decreased levels of circulating sex hormones as a biomarker of lung cancer in male patients with solitary pulmonary nodules.

BACKGROUND: An early differentiation of malignant from benign solitary pulmonary nodules (SPNs) is essential for management and prognosis of lung cancer. OBJECTIVES: Here we investigated whether measurement of circulating sex hormones could be useful for an early detection of malignancy among patients with SPNs. METHODS: We recruited 47 patients with malignant SPNs 45 patients with benign SPNs, and 32 healthy persons. Testosterone, estradiol, and progesterone were measured. Carcinoembryonic antigen (CEA) as well as TNF-α, IL-1 and IL-6 were also measured. RESULTS: We found that sex hormones were decreased significantly in patients with malignant SPNs, as compared to patients with benign SPNs and healthy controls (P<0.05). Sex hormones levels showed a trend to decline in patients with benign SPNs as compared to normal controls, but the difference was not statistically significant (P>0.05). CEA levels were only abnormally elevated in eight patients with lung adenocarcinoma. The inflammatory cytokines were remarkably higher in both patients than in normal controls. However, there was no statistical difference in these cytokines among patients. CONCLUSIONS: The reduced sex hormones levels seemed to be uniquely associated with lung cancer. Therefore, measurement of sex hormones may have clinical potential in the diagnosis of malignancy in patients with SPNs.