Combination of CT and telomerase+ circulating tumor cells improves diagnosis of small pulmonary nodules.

BACKGROUNDEarly diagnosis and treatment are key to the long-term survival of lung cancer patients. Although CT has significantly contributed to the early diagnosis of lung cancer, there are still consequences of excessive or delayed treatment. By improving the sensitivity and specificity of circulating tumor cell (CTC) detection, a solution was proposed for differentiating benign from malignant pulmonary nodules.METHODSIn this study, we used telomerase reverse transcriptase-based (TERT-based) CTC detection (TBCD) to distinguish benign from malignant pulmonary nodules < 2 cm and compared this method with the pathological diagnosis as the gold standard. FlowSight and FISH were used to confirm the CTCs detected by TBCD.RESULTSOur results suggest that CTCs based on TBCD can be used as independent biomarkers to distinguish benign from malignant nodules and are significantly superior to serum tumor markers. When the detection threshold was 1, the detection sensitivity and specificity of CTC diagnosis were 0.854 and 0.839, respectively. For pulmonary nodules ≤ 1 cm and 1-2 cm, the sensitivity and specificity of CTCs were both higher than 77%. Additionally, the diagnostic ability of CTC-assisted CT was compared by CT detection. The results show that CT combined with CTCs could significantly improve the differentiation ability of benign and malignant nodules in lung nodules < 2 cm and that the sensitivity and specificity could reach 0.899 and 0.839, respectively.CONCLUSIONTBCD can effectively diagnose pulmonary nodules and be used as an effective auxiliary diagnostic scheme for CT diagnosis.FUNDINGNational Key Research and Development Project grant nos. 2019YFC1315700 and 2017YFC1308702, CAMS Initiative for Innovative Medicine grant no. 2017-I2M-1-005, and National Natural Science Foundation of China grant no. 81472013.

Effect of a Rule-in Biomarker Test on Pulmonary Nodule Management: A Survey of Pulmonologists and Thoracic Surgeons.

INTRODUCTION: The field of biomarker development is evolving to assist in determining benign from malignant pulmonary nodules. Although a prospective clinical utility would best to show how a biomarker affects patient treatment and outcomes, we sought to begin to understand how the results might alter management by determining how physicians would use the results of a rule-in blood test to manage pulmonary nodules. MATERIALS AND METHODS: Pulmonologists and thoracic surgeons in the American College of Chest Physicians clinician database were invited to participate in an online survey. The participant demographic data were collected. Four hypothetical clinical vignettes were presented. The participants accessed the pretest probability (probability of cancer [pCA]) for malignancy and chose the management strategies as the case progressed. The management strategies chosen before and after the result of a rule-in biomarker test were compared and assessed for guideline concordance. RESULTS: Of the 455 eligible participants who had opened the survey, 416 (92%) completed it: 332 pulmonologists and 84 thoracic surgeons. Although 91% of the participants were very comfortable managing nodules, depending on the case, 30% to 62% incorrectly assessed the pCA, with 22% to 62% overestimating the risk and 8% to 51% underestimating the risk. After a rule-in blood test result, the clinician change in management moved in the right direction in some cases but, in others, the physicians used the results incorrectly. Pulmonologists and thoracic surgeons differed in the management strategies, with surgeons recommending surgery more often. CONCLUSIONS: Although the use of biomarker testing for pulmonary nodule evaluation is promising, without proper physician education, the potential for harm exists. Clinical utility studies are needed to appropriately inform the effect of biomarker use.

Comparison of four models predicting the malignancy of pulmonary nodules: A single-center study of Korean adults.

OBJECTIVE: Four commonly used clinical models for predicting the probability of malignancy in pulmonary nodules were compared. While three of the models (Mayo Clinic, Veterans Association [VA], and Brock University) are based on clinical and computed tomography (CT) characteristics, one model (Herder) additionally includes the 18F-fluorodeoxyglucose (FDG) uptake value among the positron emission tomography (PET) characteristics. This study aimed to compare the predictive power of these four models in the context of a population drawn from a single center in an endemic area for tuberculosis in Korea. METHODS: A retrospective analysis of 242 pathologically confirmed nodules (4-30 mm in diameter) in 242 patients from January 2015 to December 2015 was performed. The area under the receiver operating characteristic curve (AUC) was used to assess the predictive performance with respect to malignancy. RESULTS: Of 242 nodules, 187 (77.2%) were malignant and 55 (22.8%) were benign, with tuberculosis granuloma being the most common type of benign nodule (23/55). PET was performed for 227 nodules (93.8%). The Mayo, VA, and Brock models showed similar predictive performance for malignant nodules (AUC: 0.6145, 0.6042 and 0.6820, respectively). The performance of the Herder model (AUC: 0.5567) was not significantly different from that of the Mayo (vs. Herder, p = 0.576) or VA models (vs. Herder, p = 0.999), and there were no differences among the three models in determining the probability of malignancy of pulmonary nodules. However, compared with the Brock model, the Herder model showed a significantly lower ability to predict malignancy (adjusted p = 0.0132). CONCLUSIONS: In our study, the Herder model including the 18FDG uptake value did not perform better than the other models in predicting malignant nodules, suggesting the limited utility of adding PET/CT data to models predicting malignancy in populations within endemic areas for benign inflammatory nodules, such as tuberculosis.

Improved discrimination between benign and malignant LDCT screening-detected lung nodules with dynamic over static 18F-FDG PET as a function of injected dose.

Lung cancer mortality rate can be significantly reduced by up to 20% through routine low-dose computed tomography (LDCT) screening, which, however, has high sensitivity but low specificity, resulting in a high rate of false-positive nodules. Combining PET with CT may provide more accurate diagnosis for indeterminate screening-detected nodules. In this work, we investigated low-dose dynamic 18F-FDG PET in discrimination between benign and malignant nodules using a virtual clinical trial based on patient study with ground truth. Six patients with initial LDCT screening-detected lung nodules received 90 min single-bed PET scans following a 10 mCi FDG injection. Low-dose static and dynamic images were generated from under-sampled list-mode data at various count levels (100%, 50%, 10%, 5%, and 1%). A virtual clinical trial was performed by adding nodule population variability, measurement noise, and static PET acquisition start time variability to the time activity curves (TACs) of the patient data. We used receiver operating characteristic (ROC) analysis to estimate the classification capability of standardized uptake value (SUV) and net uptake constant K i from their simulated benign and malignant distributions. Various scan durations and start times (t *) were investigated in dynamic Patlak analysis to optimize simplified acquisition protocols with a population-based input function (PBIF). The area under curve (AUC) of ROC analysis was higher with increased scan duration and earlier t *. Highly similar results were obtained using PBIF to those using image-derived input function (IDIF). The AUC value for K i using optimized t * and scan duration with 10% dose was higher than that for SUV with 100% dose. Our results suggest that dynamic PET with as little as 1 mCi FDG could provide discrimination between benign and malignant lung nodules with higher than 90% sensitivity and specificity for patients similar to the pilot and simulated population in this study, with LDCT screening-detected indeterminate lung nodules.

The Value of 18F-FDG PET/CT Mathematical Prediction Model in Diagnosis of Solitary Pulmonary Nodules.

PURPOSE: To establish an 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) mathematical prediction model to improve the diagnosis of solitary pulmonary nodules (SPNs). MATERIALS AND METHODS: We retrospectively reviewed 177 consecutive patients who underwent 18F-FDG PET/CT for evaluation of SPNs. The mathematical model was established by logistic regression analysis. The diagnostic capabilities of the model were calculated, and the areas under the receiver operating characteristic curve (AUC) were compared with Mayo and VA model. RESULTS: The mathematical model was y = exp⁡(x)/[1 + exp⁡(x)], x = -7.363 + 0.079 × age + 1.900 × lobulation + 1.024 × vascular convergence + 1.530 × pleural retraction + 0.359 × the maximum of standardized uptake value (SUVmax). When the cut-off value was set at 0.56, the sensitivity, specificity, and accuracy of our model were 86.55%, 74.14%, and 81.4%, respectively. The area under the receiver operating characteristic curve (AUC) of our model was 0.903 (95% confidence interval (CI): 0.860 to 0.946). The AUC of our model was greater than that of the Mayo model, the VA model, and PET (P < 0.05) and has no difference with that of PET/CT (P > 0.05). CONCLUSION: The mathematical predictive model has high accuracy in estimating the malignant probability of patients with SPNs.

Localization of Pulmonary Ground-Glass Opacities with Folate Receptor-Targeted Intraoperative Molecular Imaging.

PURPOSE: Intraoperative localization and resection of ill-defined pulmonary ground-glass opacities (GGOs) during minimally invasive pulmonary resection is technically challenging. Current preoperative techniques to facilitate localization of GGOs include microcoil and hook wire placement, both of which have logistic limitations, carry safety concerns, and do not help with margin assessment. In this clinical trial, we explored an alternative method involving near-infrared molecular imaging with a folate receptor-targeted agent, OTL38, to improve localization of GGOs and confirmation of resection margins. METHODS: In a human trial, 20 subjects with pulmonary GGOs who were eligible for video-assisted thoracoscopic surgery (VATS) resection received 0.025 mg/kg of OTL38 before the resection. The primary objectives were to (1) determine whether use of OTL38 allows safe localization of GGOs and assessment of margins during VATS and (2) determine patient, radiographic, and histopathologic variables that predict the amount of fluorescence during near-infrared imaging. RESULTS: We observed no toxicity. Of the 21 GGOs, 20 accumulated OTL38 and displayed fluorescence upon in situ or back table evaluation. Intraoperatively, near-infrared imaging localized 15 of 21 lesions whereas VATS alone localized 10 of 21 (p = 0.05). The addition of molecular imaging affected care of nine of 21 subjects by improving intraoperative localization (n = 6) and identifying close margins (n = 3). This approach was most effective for subpleural lesions measuring less than 2 cm. For lesions deeper than 1.5 cm from the pleural surface, intraoperative localization using fluorescent feedback was limited. CONCLUSIONS: This approach provides a safe alternative for intraoperative localization of small, peripherally located pulmonary lesions. In contrast to alternative localization techniques, use of OTL38 also allows confirmation of adequate margins. Future studies will compare this approach to alternative localization techniques in a clinical trial.

Use of TBAg/PHA ratio in distinguishing tuberculoma from cancer in solitary pulmonary nodule or mass.

INTRODUCTION: Differentiation of tuberculoma from cancer in solitary pulmonary nodule or mass still remains a major challenge in diagnostic laboratories. OBJECTIVES: The objective of this study is to determine the performance of T-SPOT.TB assay in discriminating these 2 diseases. METHODS: We prospectively enrolled 331 patients with a solitary pulmonary nodule or mass on computed tomography scans. Conventional tests and T-SPOT.TB assay were simultaneously performed in all participants. RESULTS: Our results showed that the performance of directly using T-SPOT.TB results in distinguishing tuberculoma from cancer in solitary pulmonary nodule or mass was not satisfactory because of moderate sensitivity and specificity. However, a further calculation of the ratio of TB-specific antigen (TBAg) to phytohemagglutinin (PHA) (TBAg/PHA ratio) of T-SPOT.TB assay may lead to improvement in distinguishing these 2 diseases. If using the threshold value of 0.236, the sensitivity and specificity of the TBAg/PHA ratio in distinguishing tuberculoma from cancer in solitary pulmonary nodule or mass were, respectively, 80.6% and 93.3%. The area under the curve (AUC) of the receiver operating characteristic curve was 0.921 (95% confidence interval, 0.875-0.967). Furthermore, the TBAg/PHA ratio may also be used to distinguish tuberculoma from other benign diseases (AUC: 0.909, sensitivity: 85.07%, specificity: 90%). CONCLUSIONS: Calculation of the TBAg/PHA ratio might provide a useful non-invasive tool for distinguishing tuberculoma from cancer in patients with a solitary pulmonary nodule or mass in TB-endemic countries.

[Research Progresses of Circulating Tumor Cells in Diagnosis and Treatment of 
Early Lung Cancer].

As one of the important liquid biopsies, circulating tumor cells (CTCs) shows more and more clinical values in the treatment of lung cancer such as diagnostic screening, treatment evaluation, postoperative monitoring, and prognosis predicting etc. A large number of small pulmonary nodules patients are detected when screening the high risk population of lung cancer. However, small lung nodules are not equal to lung cancer, and 90%-95% of them are benign lesion, therefore, to accurately and correctly differentiate whether it is benign or malignant when patients firstly detected and treat a small pulmonary nodule is become a new opportunity and challenge for clinician. With the improvement of CTCs detection technology, whether it will play an important role in early differential diagnosis of lung cancer. And whether it will have clinical significance to early lung cancer surgery operations. These require further researches and explorations so as to achieve clinical transformation in the future.

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.

Nuclear localization of B7-H4 in pulmonary adenocarcinomas presenting as a solitary pulmonary nodule.

PURPOSE: Although the pathogenicity of B7-H4 in cancer is well established, its role in pulmonary adenocarcinoma, especially lesions presenting as solitary pulmonary nodules (SPNs), remains unclear. METHODS: 40 cases of pulmonary adenocarcinoma presenting with SPN were enrolled during year 2012-2015. The B7-H4 expression and its subcellular distribution in pulmonary adenocarcinoma presenting with SPN were analyzed by immunohistochemistry, further its correlation with Ki-67 expression and CT feature. In vitro, the B7-H4 expression in the cytoplasmic and nucleus fractions of lung cancer cell lines was determinate by western blotting. RESULTS: Immunostaining revealed B7-H4 in the cytoplasm of cells from all 40 SPN samples studied. No surface localization of B7-H4 was detected, but in 18 samples the nuclear membranes were B7-H4-positive. Moreover, patients with more poorly differentiated and invasive adenocarcinomas showed greater localization of B7-H4 to the nuclear membrane. The percentage of lesions with ground-glass opacity was significantly greater among samples negative for nuclear membrane B7-H4. Most importantly, there was a statistically significant relationships between the Ki-67 index and B7-H4 positivity of the nuclear membrane. This suggests tumors exhibiting higher nuclear membrane B7-H4 have greater proliferative potential. Western blotting confirmed both cytoplasmic and nuclear B7-H4 localization in lung adenocarcinoma cell lines. CONCLUSIONS: Taken together, our study provides a new insight into the tumorigenicity of B7-H4 in lung adenocarcinoma. We suggest that in pulmonary adenocarcinoma presenting with SPN, nuclear membrane localization of B7-H4 within the tumor cells is associated with increased malignancy.

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.

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.

The prognostic value of tumor shadow disappearance rate on integrated PET/CT evaluation of solitary pulmonary nodules with low glucose metabolism.

OBJECTIVE: This study aimed to determine the prognostic value of the tumor shadow disappearance rate (TDR) on integrated PET/computed tomography (PET/CT) evaluation of solitary pulmonary nodules (SPNs) with low glucose uptake. MATERIALS AND METHODS: From January 2008 to September 2010, 99 patients who underwent fluorine-18 fluorodeoxyglucose PET (F-FDG-PET)/CT scanning for the evaluation of SPNs with a maximum standardized uptake value (SUVmax) below 2.75 (2.5+10%) were retrospectively reviewed. Among the 99 SPNs from these patients, 67 were malignant and 32 were benign, based on surgical pathology. Differences in baseline characteristics between the two groups were examined by means of the independent t-test, the Mann-Whitney U-test, and the χ-test. To test the efficacy of TDR for determining malignancy, the sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and positive and negative likelihood ratios (LR+ and LR-, respectively) with 95% confidence intervals were calculated using the pathological test as the gold standard. RESULTS: Patients with malignant nodules were older than those with benign nodules (64.5 vs. 55.1 years, respectively, P<0.001) and had higher TDRs (0.8 vs. 0.3, respectively, P<0.001). The optimal cutoff point for the TDR was 0.4886 where the sensitivity, specificity, positive predictive value, and negative predictive value were 0.851, 0.844, 0.919, and 0.730, respectively, and the LR+ and LR- were 5.443 and 0177, respectively. A significant negative correlation between TDR and SUVmax was found only in the malignant group. CONCLUSION: The diagnostic value of TDR complements the PET/CT evaluation of SPNs with a low F-FDG uptake.

The role of ¹8F-FDG uptake features in the differential diagnosis of solitary pulmonary lesions with PET/CT.

BACKGROUND: The aim of this study is to evaluate the value of (18)F-FDG uptake features in the diagnosis of solitary pulmonary lesions. METHODS: One hundred thirty-nine patients with solitary pulmonary lesions were divided into full uptake, circular uptake, multi-focus uptake, mild uptake, and no-uptake groups according to the uptake features of (18)F-FDG in solitary pulmonary lesions. The incidence of benign and malignant lesions and the false-positive and false-negative rates in each group were analyzed. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of the method using (18)F-FDG uptake features combined with maximum standard uptake value (SUVmax) (SUV method) in the differential diagnosis of solitary pulmonary lesions were evaluated. RESULTS: There were 89 malignant and 50 benign lesions. (1) The malignant incidence of the full uptake group was 84.0% (63/75), and there were significant differences when compared with the other groups except the circular uptake group (16/23) (all P = 0.0001). The benign incidence of the multi-focus and no-uptake groups was 83.3% (10/12) and 82.4% (14/17), respectively, and there were significant differences when compared with the full uptake and the circular uptake groups, respectively (all P < 0.05). The benign incidence of the mild uptake group was 58.3% (7/12), and there were no significant differences when compared with the others except the full uptake group (all P > 0.05). No statistical significance was found between either two of the no-uptake, mild uptake, and multi-focus uptake groups (all P > 0.05). (2) In cases with SUVmax ≥2.5, the false-positive rate in the multi-focus uptake group was 83.3% (10/12), which was significantly higher than in the full uptake (12/75) or circular uptake group (7/23) (all P < 0.05). In cases with SUVmax <2.5, the false-negative rates in the mild and no-uptake groups were 41.7 and 17.6% (P = 0.218). (3) The sensitivity, specificity, accuracy, PPV, and NPV of the method using (18)F-FDG uptake features combined with SUVmax and the single SUV method were 88.7%/91.0%, 62.0%/42.0%, 79.1%/73.4%, 80.6%/73.6%, and 75.6%/72.4%, respectively. CONCLUSIONS: The method using uptake features of (18)F-FDG combined with SUVmax can improve the diagnostic specificity and accuracy of solitary pulmonary lesions. The multi-focus uptake feature maybe a benign sign, which still needs more researches to confirm.

MicroRNA-144 regulates proliferation, invasion, and apoptosis of cells in malignant solitary pulmonary nodule via zinc finger E-box-binding homeobox 1.

AIMS: This study was to investigate the expression of microRNA (miR)-144 in malignant solitary pulmonary nodule (SPN) tissues and peripheral blood, as well as the biological function of miR-144 in the occurrence and development of lung cancer. METHODS: In this study, 39 malignant and 30 benign SPN patients were included. The expression of miR-144 was examined using quantitative real-time polymerase chain reaction. Receiver operating characteristic (ROC) curve was used to identify the clinical value of miR-144 in the early diagnosis of malignant SPN. MTT assay was performed to determine A549 cell proliferation and Transwell assay was used to detect changes in A549 cell invasion and migration ability. Flow cytometry was performed to monitor cell apoptosis, while Western blotting assay was used to measure protein expression levels. At last, dual-luciferase reporter assay was employed to test whether miR-144 regulates zinc finger E-box-binding homeobox 1 (ZEB1) gene expression. RESULTS: Expression of miR-144 was reduced in patients with malignant SPN. miR-144 had diagnostic value for malignant SPN. Proliferation of A549 cells was inhibited by miR-144. Invasion ability of A549 cells was reduced by miR-144. Apoptosis of A549 cells was promoted by miR-144. miR-144 induced A549 cell apoptosis by targeting ZEB1 protein. miR-144 regulated the expression of ZEB1 by interacting with its 3'-UTR region. CONCLUSIONS: Expression of miR-144 is reduced in malignant SPN tissues and peripheral blood, being of clinical value in the diagnosis of malignant SPN. miR-144 promotes the apoptosis of lung cancer cells, and inhibits the proliferation, invasion and migration of lung cancer by regulating ZEB1 gene.

Establishing assistant diagnosis models of solitary pulmonary nodules based on intelligent algorithms.

AIMS: This study aimed to establish an auxiliary diagnosis model for solitary pulmonary nodules (SPNs) and evaluate its test efficacy. METHODS: Three hundred thirty-two pathologically diagnosed SPN patients (186 malignant, 146 benign) were collected as subjects. The serum levels of 8 types of markers and 9 computed tomography (CT) imaging features of each patient were treated as independent variables. The corresponding pathological classification results (fungal inflammation, tuberculosis and tuberculoma, inflammatory pseudotumor, tumor middle differentiation, cancer) of quantized patients were treated as dependent variables. A 17-to-1 mathematical auxiliary SPN diagnosis model was established using a back propagation (BP) algorithm and a support vector machine (SVM) algorithm. A 40-case test set was used to estimate the effect. RESULTS: Two different auxiliary SPN diagnosis models were successfully established. The diagnostic accuracy, sensitivity and specificity of the BP algorithm diagnosis model were 60%, 68% and 46.7%, respectively, and those of the SVM algorithm model were 80%, 85.7% and 66.7%, respectively. CONCLUSION: The accuracy, sensitivity and specificity of the SVM diagnostic model were relatively high, indicating that the model has important reference value for determining the degree of SPN differentiation and is suitable for the auxiliary diagnosis of benign and malignant SPN.

Respiratory-gated imaging in metabolic evaluation of small solitary pulmonary nodules: 18F-FDG PET/CT and correlation with histology.

OBJECTIVE: The aim of the study was to evaluate the effect of 2-((18)F)-fluoro-2-deoxy-D-glucose ((18)F-FDG)-PET/computed tomography (CT) respiratory-gated imaging [four-dimensional (4D)] in the metabolic evaluation of small solitary pulmonary nodules and analyze the cutoff maximum standardized uptake value (SUV(max)) of 2.5 in classifying and distinguishing benign/malignant pulmonary pathologies in 4D studies. MATERIALS AND METHODS: Thirty-two patients with pulmonary lesions measuring 2 cm or less were included during their scheduled (18)F-FDG PET/CT examinations. The whole-body PET/CT acquisition (3D) was followed by a chest-centered PET/CT (4D) study synchronized with the respiratory cycle. The SUV(max) percentage difference (%Diff SUV(max)) was calculated. The nodule size, localization, and relationships with histological/cytological findings were studied. RESULTS: Fifteen nodules were 10 mm or smaller and 17 were larger than 10 mm [mean size = 12 mm (7-20)]. The mean 3D-SUV(max) was 2.5 (0.7-6.1) and the mean 4D-SUV(max) 3.2 (0.9-7.2) (P < 0.001). The mean %Diff SUV(max) was 38% for all patients (7-90), 45% in subcentimetric (7-90%) and 31% (7-75%) in supracentimetric lesions (P = NS). Histology was obtained in 23/32 (72%) cases and the pathologic benign/malignant ratio was 4/19. Malignancies were diagnosed as lung adenocarcinoma, solitary metastases, large cell lung carcinoma, and sarcoma in 13 (41%), 3 (9%), 2 (6%), and 1 (3%) case, respectively. Malignant lesions showed mean 4D-SUV(max) of 3.8 (1.2-7.2). The cutoff SUV(max) of 2.5 did not classify and distinguish between benign/malignant pulmonary pathologies, neither in 3D nor in 4D studies. CONCLUSION: Respiratory gating improves the detectability and metabolic evaluation of solitary pulmonary nodules, mostly those that are subcentimetric. However, as expected, the cutoff SUV(max) of 2.5 does not distinguish between benign/malignant lesions in either 4D or 3D studies.

Change of maximum standardized uptake value slope in dynamic triphasic [18F]-fluorodeoxyglucose positron emission tomography/computed tomography distinguishes malignancy from postradiation inflammation in head-and-neck squamous cell carcinoma: a prospective trial.

PURPOSE: To evaluate dynamic [(18)F]-fluorodeoxyglucose (FDG) uptake methodology as a post-radiation therapy (RT) response assessment tool, potentially enabling accurate tumor and therapy-related inflammation differentiation, improving the posttherapy value of FDG-positron emission tomography/computed tomography (FDG-PET/CT). METHODS AND MATERIALS: We prospectively enrolled head-and-neck squamous cell carcinoma patients who completed RT, with scheduled 3-month post-RT FDG-PET/CT. Patients underwent our standard whole-body PET/CT scan at 90 minutes, with the addition of head-and-neck PET/CT scans at 60 and 120 minutes. Maximum standardized uptake values (SUV(max)) of regions of interest were measured at 60, 90, and 120 minutes. The SUV(max) slope between 60 and 120 minutes and change of SUV(max) slope before and after 90 minutes were calculated. Data were analyzed by primary site and nodal site disease status using the Cox regression model and Wilcoxon rank sum test. Outcomes were based on pathologic and clinical follow-up. RESULTS: A total of 84 patients were enrolled, with 79 primary and 43 nodal evaluable sites. Twenty-eight sites were interpreted as positive or equivocal (18 primary, 8 nodal, 2 distant) on 3-month 90-minute FDG-PET/CT. Median follow-up was 13.3 months. All measured SUV endpoints predicted recurrence. Change of SUV(max) slope after 90 minutes more accurately identified nonrecurrence in positive or equivocal sites than our current standard of SUV(max) ≥2.5 (P=.02). CONCLUSIONS: The positive predictive value of post-RT FDG-PET/CT may significantly improve using novel second derivative analysis of dynamic triphasic FDG-PET/CT SUV(max) slope, accurately distinguishing tumor from inflammation on positive and equivocal scans.

Sputum microRNA biomarkers for identifying lung cancer in indeterminate solitary pulmonary nodules.

PURPOSE: The early detection of lung cancer in heavy smokers by low-dose CT (LDCT) can reduce the mortality. However, LDCT screening increases the number of indeterminate solitary pulmonary nodules (SPN) in asymptomatic individuals, leading to overdiagnosis. Making a definitive preoperative diagnosis of malignant SPNs has been a clinical challenge. We have demonstrated that sputum miRNAs could provide potential biomarkers for lung cancer. Here, we aimed to develop sputum miRNA biomarkers for diagnosis of malignant SPNs. EXPERIMENTAL DESIGN: Using quantitative RT-PCR, we evaluated expressions of 13 sputum miRNAs, previously identified sputum miRNA signatures of lung cancer, in a training set of 122 patients with either malignant (n = 60) or benign SPNs (n = 62) to define a panel of biomarkers. We then validated the biomarker panel in an internal testing set of 136 patients with either malignant (n = 67) or benign SPNs (n = 69), and an external testing cohort of 155 patients with either malignant (n = 76) or benign SPNs (n = 79). RESULTS: In the training set, a panel of three miRNA biomarkers (miRs21, 31, and 210) was developed, producing 82.93% sensitivity and 87.84% specificity for identifying malignant SPNs. The sensitivity and specificity of the biomarkers in the two independent testing cohorts were 82.09% and 88.41%, 80.52% and 86.08%, respectively, confirming the diagnostic value. CONCLUSIONS: Sputum miRNA biomarkers may improve LDCT screening for lung cancer in heavy smokers by preoperatively diagnosing malignant SPNs. Nevertheless, a prospective study in a large population to validate the biomarkers is needed.