Epigenetic imprinting alterations as effective diagnostic biomarkers for early-stage lung cancer and small pulmonary nodules

Abstract Background Early lung cancer detection remains a clinical challenge for standard diagnostic biopsies due to insufficient tumor morphological evidence. As epigenetic alterations precede morphological changes, expression alterations of certain imprinted genes could serve as actionable diagnostic biomarkers for malignant lung lesions. Results Using the previously established quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) method, elevated aberrant allelic expression of imprinted genes GNAS, GRB10, SNRPN and HM13 was observed in lung cancers over benign lesions and normal controls, which were pathologically confirmed among histologically stained normal, paracancerous and malignant tissue sections. Based on the differential imprinting signatures, a diagnostic grading model was built on 246 formalin-fixed and paraffin-embedded (FFPE) surgically resected lung tissue specimens, tested against 30 lung cytology and small biopsy specimens, and blindly validated in an independent cohort of 155 patients. The QCIGISH diagnostic model demonstrated 99.1% sensitivity (95% CI 97.5–100.0%) and 92.1% specificity (95% CI 83.5–100.0%) in the blinded validation set. Of particular importance, QCIGISH achieved 97.1% sensitivity (95% CI 91.6–100.0%) for carcinoma in situ to stage IB cancers with 100% sensitivity and 91.7% specificity (95% CI 76.0–100.0%) noted for pulmonary nodules with diameters ≤ 2 cm. Conclusions Our findings demonstrated the diagnostic value of epigenetic imprinting alterations as highly accurate translational biomarkers for a more definitive diagnosis of suspicious lung lesions.

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Circulating serum exosomal miR-20b-5p and miR-3187-5p as efficient diagnostic biomarkers for early-stage non-small cell lung cancer

Experimental Biology and Medicine ◽

10.1177/1535370220945987 ◽

2020 ◽

Vol 245 (16) ◽

pp. 1428-1436

Author(s):

Zhi-Jun Zhang ◽

Xing-Guo Song ◽

Li Xie ◽

Kang-Yu Wang ◽

You-Yong Tang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Early Stage ◽

Small Cell ◽

Small Cell Lung ◽

Diagnostic Biomarkers ◽

Non Invasive ◽

Early Stage Nsclc ◽

Nsclc Patients

Circulating exosomal microRNAs (ExmiRNAs) provide an ideal non-invasive method for cancer diagnosis. In this study, we evaluated two circulating ExmiRNAs in NSCLC patients as a diagnostic tool for early-stage non-small lung cancer (NSCLC). The exosomes were characterized by qNano, transmission electron microscopy, and Western blot, and the ExmiRNA expression was measured by microarrays. The differentially expressed miRNAs were verified by RT-qPCR using peripheral blood specimens from NSCLC patients ( n = 276, 0 and I stage: n = 104) and healthy donors ( n = 282). The diagnostic values were measured by receiver operating characteristic (ROC) analysis. The results show that the expression of both ExmiR-20b-5p and ExmiR-3187-5p was drastically reduced in NSCLC patients. The area under the ROC curve (AUC) was determined to be 0.818 and 0.690 for ExmiR-20b-5p and ExmiR-3187-5p, respectively. When these two ExmiRNAs were combined, the AUC increased to 0.848. When the ExmiRNAs were administered with either carcinoembryonic antigen (CEA) or cytokeratin-19-fragment (CYFRA21-1), the AUC was further improved to 0.905 and 0.894, respectively. Additionally, both ExmiR-20b-5p and ExmiR-3187-5p could be used to distinguish early stages NSCLC (0 and I stage) from the healthy controls. The ROC curves showed that the AUCs were 0.810 and 0.673, respectively. Combination of ExmiR-20b-5p and ExmiR-3187-5p enhanced the AUC to 0.838. When CEA and CYFRA21-1 were administered with the ExmiRNAs, the AUCs were improved to 0.930 and 0.928, respectively. In summary, circulating serum exosomal miR-20b-5p and miR-3187-5p could be used as effective, non-invasive biomarkers for the diagnosis of early-stage NSCLC, and the effects were further improved when the ExmiRNAs were combined. Impact statement The high mortality of non-small cell lung cancer (NSCLC) is mainly because the cancer has progressed to a more advanced stage before diagnosis. If NSCLC can be diagnosed at early stages, especially stage 0 or I, the overall survival rate will be largely improved by definitive treatment such as lobectomy. We herein validated two novel circulating serum ExmiRs as diagnostic biomarkers for early-stage NSCLC to fulfill the unmet medical need. Considering the number of specimens in this study, circulating serum exosomal miR-20b-5p and miR-3187-5p are putative NSCLC biomarkers, which need to be further investigated in a larger randomized controlled clinical trial.

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Effect of a pulmonary nodule fact sheet on patient anxiety and knowledge: a quality improvement initiative

BMJ Open Quality ◽

10.1136/bmjoq-2018-000437 ◽

2018 ◽

Vol 7 (3) ◽

pp. e000437 ◽

Cited By ~ 4

Author(s):

Matthew T Koroscil ◽

Mitchell H Bowman ◽

Michael J Morris ◽

Andrew J Skabelund ◽

Andrew M Hersh

Keyword(s):

Lung Cancer ◽

Quality Improvement ◽

Pulmonary Nodule ◽

Early Stage ◽

Pulmonary Nodules ◽

Low Risk ◽

Quality Improvement Initiative ◽

Patient Anxiety ◽

Patient Understanding ◽

Fact Sheet

IntroductionThe utilisation of chest CT for the evaluation of pulmonary disorders, including low-dose CT for lung cancer screening, is increasing in the USA. As a result, the discovery of both screening-detected and incidental pulmonary nodules has become more frequent. Despite an overall low risk of malignancy, pulmonary nodules are a common cause of emotional distress among adult patients.MethodsWe conducted a multi-institutional quality improvement (QI) initiative involving 101 participants to determine the effect of a pulmonary nodule fact sheet on patient knowledge and anxiety. Males and females aged 35 years or older, who had a history of either screening-detected or incidental solid pulmonary nodule(s) sized 3–8 mm, were included. Prior to an internal medicine or pulmonary medicine clinic visit, participants were given a packet containing a pre-fact sheet survey, a pulmonary nodule fact sheet and a post-fact sheet survey.ResultsOf 101 patients, 61 (60.4%) worried about their pulmonary nodule at least once per month with 18 (17.8%) worrying daily. The majority 67/101 (66.3%) selected chemotherapy, chemotherapy and radiation, or radiation as the best method to cure early-stage lung cancer. Despite ongoing radiographic surveillance, 16/101 (15.8%) stated they would not be interested in an intervention if lung cancer was diagnosed. Following review of the pulmonary nodule fact sheet, 84/101 (83.2%) reported improved anxiety and 96/101 (95.0%) reported an improved understanding of their health situation. Patient understanding significantly improved from 4.2/10.0 to 8.1/10.0 (p<0.01).ConclusionThe incorporation of a standardised fact sheet for subcentimeter solid pulmonary nodules improves patient understanding and alleviates anxiety. We plan to implement pulmonary nodule fact sheets into the care of our patients with low-risk subcentimeter pulmonary nodules.

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Reducing False-Positives in Lung Nodules Detection Using Balanced Datasets

Frontiers in Public Health ◽

10.3389/fpubh.2021.671070 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jinglun Liang ◽

Guoliang Ye ◽

Jianwen Guo ◽

Qifan Huang ◽

Shaohui Zhang

Keyword(s):

Lung Cancer ◽

Early Stage ◽

Pulmonary Nodules ◽

Ct Images ◽

False Positives ◽

Classification Systems ◽

Cad System ◽

Nodule Detection ◽

Diagnosis Of Lung Cancer ◽

Lung Ct

Malignant pulmonary nodules are one of the main manifestations of lung cancer in early CT image screening. Since lung cancer may have no early obvious symptoms, it is important to develop a computer-aided detection (CAD) system to assist doctors to detect the malignant pulmonary nodules in the early stage of lung cancer CT diagnosis. Due to the recent successful applications of deep learning in image processing, more and more researchers have been trying to apply it to the diagnosis of pulmonary nodules. However, due to the ratio of nodules and non-nodules samples used in the training and testing datasets usually being different from the practical ratio of lung cancer, the CAD classification systems may easily produce higher false-positives while using this imbalanced dataset. This work introduces a filtering step to remove the irrelevant images from the dataset, and the results show that the false-positives can be reduced and the accuracy can be above 98%. There are two steps in nodule detection. Firstly, the images with pulmonary nodules are screened from the whole lung CT images of the patients. Secondly, the exact locations of pulmonary nodules will be detected using Faster R-CNN. Final results show that this method can effectively detect the pulmonary nodules in the CT images and hence potentially assist doctors in the early diagnosis of lung cancer.

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Non-surgical management of early-stage lung cancer

10.1093/med/9780199657742.003.0004 ◽

2017 ◽

Author(s):

Jim Brown ◽

Neal Navani

Keyword(s):

Lung Cancer ◽

Early Stage ◽

Pulmonary Nodules ◽

The Elderly ◽

Multidisciplinary Teams ◽

Solitary Pulmonary Nodules ◽

Early Stage Lung Cancer ◽

Mortality And Morbidity ◽

Inoperable Patient ◽

Ablative Techniques

As low-dose computed tomography screening of ‘high-risk’ smokers is occurring with increasing frequency, the incidental discovery of solitary pulmonary nodules is becoming more frequent, and lung cancer multidisciplinary teams are now often faced with balancing risk and benefit when making decisions regarding the radical treatment of patients with a clinical diagnosis of early lung cancer but borderline fitness. Surgery offers the best prospect of cure but is associated with significant mortality and morbidity; the elderly and frail experience more toxicity and a greater impact on the quality of life. This chapter reviews the criteria for assessing surgical fitness and examines the evidence for minimally invasive and ablative techniques for the treatment of early peripheral lung cancer in the medically inoperable patient.

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Diagnosis and outcome of resected solitary pulmonary nodules after liver transplantation

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyz159 ◽

2019 ◽

Author(s):

Mari Tone ◽

Nobuyasu Awano ◽

Takehiro Izumo ◽

Hanako Yoshimura ◽

Tatsunori Jo ◽

...

Keyword(s):

Computed Tomography ◽

Lung Cancer ◽

Liver Transplantation ◽

Early Stage ◽

Lung Resection ◽

Invasive Pulmonary Aspergillosis ◽

Primary Lung Cancer ◽

Pulmonary Nodules ◽

Solitary Pulmonary Nodules ◽

Computed Tomography Scans

Abstract Objective Solitary pulmonary nodules after liver transplantation are challenging clinical problems. Herein, we report the causes and clinical courses of resected solitary pulmonary nodules in patients who underwent liver transplantation. Methods We retrospectively obtained medical records of 68 patients who underwent liver transplantation between March 2009 and June 2016. This study mainly focused on patients with solitary pulmonary nodules observed on computed tomography scans during follow-ups that were conducted until their deaths or February 2019. Results Computed tomography scans revealed solitary pulmonary nodules in 7 of the 68 patients. Definitive diagnoses were obtained using video-assisted lung resection in all seven patients. None experienced major postoperative complications. The final pathologic diagnoses were primary lung cancer in three patients, pulmonary metastases from hepatocellular carcinoma in one patient, invasive pulmonary aspergillosis in one patient, post-transplant lymphoproliferative disorder in one patient, and hemorrhagic infarction in one patient. The three patients with lung cancer were subsequently treated with standard curative resection. Conclusions Solitary pulmonary nodules present in several serious but potentially curable diseases, such as early-stage lung cancer. Patients who present with solitary pulmonary nodules after liver transplantation should be evaluated by standard diagnostic procedures, including surgical biopsy if necessary.

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

10.21203/rs.2.17762/v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jian Zheng ◽

Xiong Ye ◽

Yuxia Zhao ◽

Mudan He ◽

Hui Xiao

Keyword(s):

Lung Cancer ◽

Sensitivity And Specificity ◽

Radiographic Finding ◽

Gene Copy Number ◽

Area Under The Curve ◽

Pulmonary Nodules ◽

Gene Copy ◽

Solitary Pulmonary Nodules ◽

Diagnostic Efficacy ◽

Diagnostic Biomarkers

Abstract 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 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, sub solid nodules and nodules ≥8 mm.Conclusion: 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, sub solid nodules and nodules ≥8 mm.

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Tumor-derived exosomal miR-155-5p and miR-658 in serum as diagnostic biomarkers for early-stage non-small cell lung cancer

10.21203/rs.3.rs-40703/v1 ◽

2020 ◽

Author(s):

ZhiJun Zhang ◽

XingGuo Song ◽

Li Xie ◽

KangYu Wang ◽

YouYong Tang ◽

...

Keyword(s):

Lung Cancer ◽

Early Stage ◽

Small Cell ◽

Small Cell Lung ◽

Diagnostic Biomarkers ◽

Early Stage Nsclc ◽

Healthy Donors ◽

Diagnostic Capacity ◽

Auc Value ◽

Nsclc Patients

Abstract Background Exosomal microRNAs (ExmiRNAs) provided a non-invasive and ideal method for cancer diagnosis. However, few studies identified the role of specific serum ExmiRNAs profiles in early non-small cell lung cancer (NSCLC) diagnosis, especially for 0 and I stage. Herein, the present study was designed to validate the novel serum ExmiRNAs as diagnostic biomarkers for early-stage NSCLC. Methods Serum exosomes were collected from the healthy donors and NSCLC patients by ultracentrifugation, and characterized with qNano, TEM, and western immunoblotting. Exosomal RNAs were subjected to miRNA array for evaluating the expression levels of miRNAs. Partly differently expressed serum exosomal miRNAs were verified by large-scale samples from 312 healthy donors and 318 NSCLC patients. Results The expression levels of ExmiR-155-5p and ExmiR-658 were significantly down-regulated in NSCLC patients compared to healthy donors (p < 0.0001 and p < 0.0001, respectively), and they could differentiate NSCLC patients from healthy donors with area under the ROC curve (AUC) of 0.716 and 0.728, respectively. In addition, combination of ExmiR-155-5p and ExmiR-658 could improve the diagnostic capacity with AUC value of 0.781. Moreover, ExmiR-155-5p and ExmiR-658 could differentiate early-stage NSCLC patients (0 and I stage) from healthy donors with AUC values of 0.668 and 0.735, respectively, combination could improve the diagnostic capacity with AUC value of 0.759. Specifically, the expression of ExmiR-155-5p was significantly decreased in patients with lymph node metastasis and distant metastasis (p = 0.0018 and p = 0.0077, respectively). Conclusions Our results identified that serum ExmiR-155-5p and ExmiR-658 were promising diagnostic biomarkers for early-stage NSCLC, and combination of them could improve the diagnostic capacity.

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The Role of IGF-Pathway Biomarkers in Determining Risks, Screening, and Prognosis in Lung Cancer: A Systematic Review.

10.21203/rs.3.rs-952465/v1 ◽

2021 ◽

Author(s):

Alexander W. Pohlman ◽

Hita Moudgalya ◽

Lia Jordano ◽

Gabriela C. Lobato ◽

David Gerard ◽

...

Keyword(s):

Lung Cancer ◽

Early Stage ◽

Pulmonary Nodules ◽

Lung Cancer Screening ◽

Smoking History ◽

Early Stage Lung Cancer ◽

Detection Rates ◽

Variable Expression ◽

Igf I ◽

Igfbp 3

Abstract Background: Detection rates of early-stage lung cancer are traditionally low, which contributes to inconsistent treatment responses and the highest rates of annual cancer deaths in the U.S. Currently, age and smoking history are the primary factors that qualify patients for low-dose computed tomography (LDCT) screening, which contributes heavily to a high false discovery rate. This limitation to the current screening paradigm has prompted research to identify biomarkers that will help more clearly define eligible patients for LDCT screening, differentiate indeterminate pulmonary nodules, and select individualized cancer therapy. Biomarkers within the Insulin-like Growth Factor (IGF) family have come to the forefront of this research. Methods: Literature available through PubMed and Google Scholar sources was cataloged using keywords: {Lung Cancer} AND {IGF} AND {Risk OR Diagnosis OR Prognosis OR Prognostication OR Treatment}. The results were summarized and provided herein.Results: Multiple biomarkers within the IGF family (or axis) have been investigated, most notably IGF-I and IGF binding protein 3 (IGFBP-3). However, newer studies seek to expand this search to other molecules within the IGF axis. Results have differed, however, due to features such as the pre-disease variable expression of IGF-I and IGFBP-3, likely promoted by factors such as obesity and smoking history. Certain studies have demonstrated these biomarkers are useful as a companion test alongside lung cancer screening, but other findings were not as conclusive, possibly owing to measurement bias from pre-analytical variables and non-standardized assay techniques. Research also has suggested IGF biomarkers may be beneficial in the prognostication and subsequent application of treatment via systemic therapy. Despite these advances, however, additional knowledge as to the intricacies of regulatory mechanisms inherent to this system are necessary to more fully harness the potential clinical utility for diagnostic tests and to identify novel targets for therapeutic intervention. Conclusions: The IGF system likely plays a role in multiple phases of lung cancer; however, there is a surplus of conflicting data, especially prior to development of the disease and during early stages of detection. IGF biomarkers may be valuable in the screening, prognosis, and treatment of lung cancer, though their exact application requires further study.

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Detection of circulating genetically abnormal cells using 4-color fluorescence in situ hybridization for the early detection of lung cancer

10.21203/rs.3.rs-69939/v1 ◽

2020 ◽

Author(s):

Mingxiang Feng ◽

Xin Ye ◽

Miao Lin ◽

Haining Zhou ◽

Meng Huang ◽

...

Keyword(s):

Lung Cancer ◽

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Pulmonary Nodules ◽

Diagnostic Value ◽

Pathological Examination ◽

Operating Characteristics ◽

Diagnostic Values ◽

Abnormal Cells

Abstract Background Available biomarkers lack sensitivity for early lung cancer. Circulating genetically abnormal cells (CACs) occur early in tumorigenesis. To determine the diagnostic value of CACs in blood detected by 4-color fluorescence in situ hybridization (FISH) for lung cancer. Methods This was a prospective study of patients with pulmonary nodules ≤ 30 mm detected between 10/2019 and 01/2020 at four tertiary hospitals in China. All patients underwent a pathological examination of lung nodules found by imaging and were grouped as malignant and benign. CACs were detected by 4-color FISH. Patients were divided into the training and validation cohorts. Receiver operating characteristics analysis was used to analyze the diagnosis value of CACs. Results A total of 205 participants were enrolled. Using a cut-off value of ≥ 3, blood CACs achieved areas under the curve (AUCs) of 0.887, 0.823, and 0.823 for lung cancer in the training and validation cohorts, and all patients, respectively. CACs had high diagnostic values across all tumor sizes and imaging lesion types. CACs were decreased after surgery (median, 4 vs. 1, P < 0.001) in the validation set. The CAC status between blood and tissues was highly consistent (kappa = 0.909, P < 0.001). The AUC of CAC (0.823) was higher than that of CEA (0.478), SCC (0.516), NSE (0.506), ProGRP (0.519), and CYFRA21-1 (0.535) (all P < 0.001). Conclusions CACs might have a high value for the early diagnosis of lung cancer. These findings might need to be validated in future studies. Evidence suggested homology in genetic aberrations between the CACs and the tumor cells.

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A segmentation of pulmonary nodules based on improved fuzzy C-means clustering algorithm

MATEC Web of Conferences ◽

10.1051/matecconf/201823203011 ◽

2018 ◽

Vol 232 ◽

pp. 03011 ◽

Cited By ~ 1

Author(s):

Tiejun Yang ◽

Jinfeng Cheng ◽

Chunhua Zhu

Keyword(s):

Lung Cancer ◽

Information Needs ◽

Clustering Algorithm ◽

Early Stage ◽

Human Life ◽

Pulmonary Nodules ◽

Local Domain ◽

Fuzzy C Means ◽

Fuzzy C Means Clustering ◽

Aided Diagnosis

According to reports, lung cancer is gradually becoming the first cancer that threatens human life. The early stage of lung cancer is in the form of pulmonary nodules. The key issue in computer-aided diagnosis of lung tumors is to correct and accelerate rapid segmentation of diseased tissue. Therefore, this paper proposes a robust fuzzy c-mean clustering algorithm for pulmonary nodules segmentation, which can effectively improve the adaptive degree of local domain pixels. Since the information of the domain pixels does not necessarily have a positive correlation with the central pixels, the reference mechanism of domain window pixel information needs to be redefined. The robust fuzzy c-means clustering algorithm redefines the grayscale of the spatial pixel points in the domain and selects different fuzzy factors according to the reference standard. Based on this, the weights of different fuzzy factors are updated according to the characteristics of pixel points and gray fluctuation in pixel domain. The experimental results show that this method is superior to other typical algorithms in the segmentation of pulmonary nodules.

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