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Zhao Y, Zhang Z, Qiu JH, Li RY, Sun ZG. Catching cancer signals in the blood: Innovative pathways for early esophageal cancer diagnosis. World J Gastroenterol 2025; 31:101838. [PMID: 40093671 PMCID: PMC11886526 DOI: 10.3748/wjg.v31.i10.101838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 01/23/2025] [Accepted: 02/05/2025] [Indexed: 02/26/2025] Open
Abstract
In recent years, significant progress has been made in the application of DNA methylation for the early detection of esophageal cancer (EC). As an epigenetic modification, DNA methylation allows for noninvasive screening by detecting the methylation status of circulating tumor DNA. Studies have shown that the methylation of genes such as SHOX2, SEPTIN9, EPO, and RNF180 significantly improves diagnostic sensitivity and specificity. Currently, SEPTIN9 has been approved by the Food and Drug Administration for colorectal cancer screening, while SHOX2 and EPO show promising results in EC, and RNF180 has potential in gastrointestinal tumors. This editorial reviews the study by Liu et al, which demonstrated the potential of combining the methylation of these four genes for early EC screening. In addition to their roles in early diagnosis, DNA methylation markers are gaining attention because of their roles in predicting recurrence and in postoperative follow-up. By monitoring changes in methylation levels, these markers can provide valuable insights into treatment efficacy and long-term management. As research progresses, liquid biopsy technology is expected to become an essential tool in the precision diagnosis and treatment of EC, benefiting patients significantly.
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Affiliation(s)
- Yue Zhao
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan 250063, Shandong Province, China
| | - Zhan Zhang
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan 250063, Shandong Province, China
| | - Jian-Hao Qiu
- Department of Thoracic Surgery, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan 250063, Shandong Province, China
| | - Rong-Yang Li
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan 250063, Shandong Province, China
| | - Zhen-Guo Sun
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan 250063, Shandong Province, China
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Peng M, Yang L, Liao J, Le X, Dai F, Sun R, Wu F, Jiang Y, Tian R, Shao B, Zhou L, Wu M, Guo S, Xiang T. The novel DNA methylation marker FIBIN suppresses non-small cell lung cancer metastasis by negatively regulating ANXA2. Cell Signal 2024; 120:111197. [PMID: 38697447 DOI: 10.1016/j.cellsig.2024.111197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 04/10/2024] [Accepted: 04/28/2024] [Indexed: 05/05/2024]
Abstract
OBJECTIVES The clinical T1 stage solid lung cancer with metastasis is a serious threat to human life and health. In this study, we performed RNA sequencing on T1 advanced-stage lung cancer and adjacent tissues to identify a novel biomarker and explore its roles in lung cancer. METHODS Quantitative reversed-transcription PCR, reverse transcription PCR and Western blot, MSP and Methtarget were utilized to evaluate FIBIN expression levels at both the transcriptional and protein levels as well as its methylation status. Differential target protein was evaluated for relative and absolute quantitation by isobaric tags. Co-IP was performed to detect the interactions between target protein. Precise location and expression levels of target proteins were revealed by immunofluorescence staining and component protein extraction using specific kits, respectively. RESULTS We reported that FIBIN was frequently silenced due to promoter hypermethylation in lung cancer. Additionally, both in vitro and in vivo experiments confirmed the significant anti-proliferation and anti-metastasis capabilities of FIBIN. Mechanistically, FIBIN decreased the nuclear accumulation of β-catenin by reducing the binding activity of GSK3β with ANXA2 while promoting interaction between GSK3β and β-catenin. CONCLUSION Our findings firstly identify FIBIN is a tumor suppressor, frequently silenced due to promoter hypermethylation. FIBIN may serve as a predictive biomarker for progression or metastasis among early-stage lung cancer patients.
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MESH Headings
- Animals
- Female
- Humans
- Male
- Mice
- A549 Cells
- Annexin A2/metabolism
- Annexin A2/genetics
- beta Catenin/metabolism
- Biomarkers, Tumor/metabolism
- Biomarkers, Tumor/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- DNA Methylation
- Gene Expression Regulation, Neoplastic
- Glycogen Synthase Kinase 3 beta/metabolism
- Lung Neoplasms/pathology
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Metastasis
- Promoter Regions, Genetic/genetics
- Glycoproteins/genetics
- Cell Cycle Proteins/genetics
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Affiliation(s)
- Mingyu Peng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Li Yang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jiaxin Liao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xin Le
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Fengsheng Dai
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ran Sun
- Department of Oncology, Jiulongpo People's Hospital, Chongqing 400050, China
| | - Fan Wu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yu Jiang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Rui Tian
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Bianfei Shao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Li Zhou
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Mingjun Wu
- Institute of Life Science, Chongqing Medical University, Chongqing 400016, China.
| | - Shuliang Guo
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
| | - Tingxiu Xiang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
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Lan Z, Zhang J, Yang F, Ma X, He R. Utility of SHOX2 and RASSF1A gene methylation detection on the residual cytology material from endobronchial ultrasound-guided transbronchial needle aspiration. Cytojournal 2024; 21:19. [PMID: 38887695 PMCID: PMC11181472 DOI: 10.25259/cytojournal_114_2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 03/29/2024] [Indexed: 06/20/2024] Open
Abstract
Objective This study aims to assess the effectiveness of Short Stature Homeobox 2 (SHOX2) and RAS Association Domain Family 1 Isoform A (RASSF1A) gene methylation detection in residual liquid-based cytology (LBC) materials from Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) and investigate the diagnostic accuracy of a comprehensive diagnostic approach. Material and Methods Between June 2022 and May 2023, a total of 110 cases that underwent EBUS-TBNA were enrolled in the study. SHOX2 and RASSF1A genes methylation detection using the residual cytological material, LBC, and cell block (CB) were conducted for each EBUS-TBNA case. The sensitivity and specificity of cytology, CB histopathology, SHOX2, and RASSF1A methylation in diagnosing EBUS-TBNA samples were determined based on follow-up data. Results Among the 72 cases confirmed as pulmonary carcinomas, the methylation test yielded positive results in 24 adenocarcinoma cases, 10 squamous cell carcinoma cases, and 14 small cell carcinoma cases. The sensitivity of the comprehensive diagnosis (combining LBC, CB, and methylation detection) in distinguishing metastatic pulmonary epithelial malignancies in mediastinal and hilar lymph nodes or masses from benign lesions was higher (97.22%, 70/72) than that of morphological diagnosis alone (LBC and CB) (88.89%, 64/72; P < 0.05). Conclusion SHOX2 and RASSF1A methylation detection demonstrates a high sensitivity and negative predictive value in the identification of pulmonary epithelial malignancies and holds promise as a valuable ancillary approach to enhance morphological diagnosis of EBUS-TBNA.
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Affiliation(s)
- Zhihua Lan
- Department of Pathology, the First Affiliated Hospital of Hengyang Medical School, Hengyang, Hunan, China
| | - Jing Zhang
- Department of Pathology, the First Affiliated Hospital of Hengyang Medical School, Hengyang, Hunan, China
| | - Fang Yang
- Department of Anorectal Surgery in Traditional Chinese Medicine, the First Affiliated Hospital of Hengyang Medical School, Hengyang, Hunan, China
| | - Xin Ma
- Department of Pathology, the First Affiliated Hospital of Hengyang Medical School, Hengyang, Hunan, China
| | - Rongfang He
- Department of Pathology, the First Affiliated Hospital of Hengyang Medical School, Hengyang, Hunan, China
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Xie B, Dong W, He F, Peng F, Zhang H, Wang W. The Combination of SHOX2 and RASSF1A DNA Methylation Had a Diagnostic Value in Pulmonary Nodules and Early Lung Cancer. Oncology 2024; 102:759-774. [PMID: 38262380 DOI: 10.1159/000534275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 09/19/2023] [Indexed: 01/25/2024]
Abstract
INTRODUCTION The study explored the effects of SHOX2 and RASSF1A DNA methylation in lung cancer (LC). METHOD Bronchoalveolar lavage fluid (BALF) samples as well as LC and normal adjacent tissues were collected from 72 LC patients and 35 patients with benign pulmonary nodules. Quantitative analysis of SHOX2 and RASSF1A DNA methylation was performed in benign pulmonary nodules and different stages of LC. The diagnostic value of SHOX2 and RASSF1A DNA methylation in LC and benign pulmonary nodules was determined by receiver operating characteristics analysis. Gain/loss-of-function experiments were constructed in LC cells and mouse models of xenograft and pulmonary nodule metastasis. The levels of SHOX2 and transfer-associated genes were tested through quantitative reverse transcription polymerase chain reaction and Western blot. Malignant phenotype of LC cells was assessed by functional experiment. The tumor volume and weight of mice in xenograft models were measured. Pulmonary nodule metastasis was determined through HE staining assay. 5-azacytidine appeared as a positive control drug. RESULT SHOX2 DNA methylation or RASSF1A DNA methylation had diagnostic efficiency in pulmonary nodules and early LC, with the two combined having better diagnostic value. SHOX2 expression was upregulated in LC. Similar to 5-azacytidine, SHOX2 knockdown inhibited LC cell viability, migration, and invasion in vitro as well as restrained LC tumorigenesis and pulmonary nodule metastasis in vivo, whereas overexpressed SHOX2 had the opposite effects. CONCLUSION The combination of SHOX2 and RASSF1A DNA methylation had a diagnostic value in pulmonary nodules and early LC. SHOX2 positively modulated the tumorigenesis and metastasis of LC by regulating DNA methylation processes.
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Affiliation(s)
- Bin Xie
- Department of Respiratory Medicine, Yue Bei People's Hospital, Shaoguan, China
| | - Wenyan Dong
- Department of Geriatric Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fengping He
- Central Laboratory, Yue Bei People's Hospital, Shaoguan, China
| | - Feng Peng
- Department of Respiratory Medicine, Yue Bei People's Hospital, Shaoguan, China
| | - Honghua Zhang
- Department of Respiratory Medicine, Yue Bei People's Hospital, Shaoguan, China
| | - Wei Wang
- Medical Integration and Practice Center of Shandong University, Jinan, China
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Ji XY, Li H, Chen HH, Lin J. Diagnostic performance of RASSF1A and SHOX2 methylation combined with EGFR mutations for differentiation between small pulmonary nodules. J Cancer Res Clin Oncol 2023; 149:8557-8571. [PMID: 37097393 DOI: 10.1007/s00432-023-04745-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/03/2023] [Indexed: 04/26/2023]
Abstract
BACKGROUND AND AIM Aberrant methylation of Ras association domain family 1, isoform A (RASSF1A), and short-stature homeobox gene 2 (SHOX2) promoters has been validated as a pair of valuable biomarkers for diagnosing early lung adenocarcinomas (LUADs). Epidermal growth factor receptor (EGFR) is the key driver mutation in lung carcinogenesis. This study aimed to investigate the aberrant promoter methylation of RASSF1A and SHOX2, and the genetic mutation of EGFR in 258 specimens of early LUADs. METHODS We retrospectively selected 258 paraffin-embedded samples of pulmonary nodules measuring 2 cm or less in diameter and evaluated the diagnostic performance of individual biomarker assays and multiple panels between noninvasive (group 1) and invasive lesions (groups 2A and 2B). Then, we investigated the interaction between genetic and epigenetic alterations. RESULTS The degree of RASSF1A and SHOX2 promoter methylation and EGFR mutation was significantly higher in invasive lesions than in noninvasive lesions. The three biomarkers distinguished between noninvasive and invasive lesions with reliable sensitivity and specificity: 60.9% sensitivity [95% confidence interval (CI) 52.41-68.78] and 80.0% specificity (95% CI 72.14-86.07). The novel panel biomarkers could further discriminate among three invasive pathological subtypes (area under the curve value > 0.6). The distribution of RASSF1A methylation and EGFR mutation was considerably exclusive in early LUAD (P = 0.002). CONCLUSION DNA methylation of RASSF1A and SHOX2 is a pair of promising biomarkers, which may be used in combination with other driver alterations, such as EGFR mutation, to support the differential diagnosis of LUADs, especially for stage I.
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Affiliation(s)
- Xiang-Yu Ji
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China
| | - Hong Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Hui-Hui Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jie Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
- National Virtual and Reality Experimental Education Center for Medical Morphology, Southern Medical University, Guangzhou, People's Republic of China.
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Zhang J, Huang H, Yu F, Bian Y, Wang R, Liu H, Kang S, She B, Shi Z. A comprehensive diagnostic scheme of morphological combined molecular methylation under bronchoscopy. Front Oncol 2023; 13:1133675. [PMID: 37182143 PMCID: PMC10174301 DOI: 10.3389/fonc.2023.1133675] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 04/12/2023] [Indexed: 05/16/2023] Open
Abstract
Methylated SHOX2 and RASSF1A genes are potential biomarkers for lung cancer diagnosis. Therefore, we explored the role of methylation detection combined with morphological bronchoscopic evaluation for lung cancer diagnosis. Bronchoscopy, methylation outcome, and pathological data were collected from 585 patients with lung cancer and 101 controls. The methylation status of the SHOX2 and RASSF1A genes were detected using real-time polymerase chain reaction quantification. Further, the sensitivity and area under the receiver operating characteristic curve of the three methods were analyzed. Among 686 patients, 57.1% had new lesions detected through bronchoscopy and 93.1% of these patients were diagnosed with malignant tumors. Besides, 42.9% of patients had no visible changes under bronchoscopy but there were still 74.8% of them diagnosed with malignant tumors. Bronchoscopy revealed that lung adenocarcinoma, lung squamous cell carcinoma, and small cell lung cancer mainly occurred in the upper and middle lobes. The sensitivity and specificity of methylation detection were 72.8% and 87.1% (vs. cytology 10.4% & 100%), respectively. Therefore, methylated SHOX2 and RASSF1A genes may be promising tumor markers in lung cancer diagnosis. Methylation detection can be an excellent supplementary tool for cytological diagnosis and, combined with bronchoscopy, could form a more effective diagnostic process.
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Affiliation(s)
- Jinze Zhang
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Haoran Huang
- Department of Academic Development, Tellgen Corporation, Shanghai, China
| | - Fan Yu
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuanyuan Bian
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Rui Wang
- The Cancer Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hui Liu
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Saisai Kang
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bin She
- Department of Academic Development, Tellgen Corporation, Shanghai, China
| | - Zhihua Shi
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Islam A, Shaukat Z, Hussain R, Gregory SL. One-Carbon and Polyamine Metabolism as Cancer Therapy Targets. Biomolecules 2022; 12:biom12121902. [PMID: 36551330 PMCID: PMC9775183 DOI: 10.3390/biom12121902] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/09/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key output of one-carbon metabolism with widespread effects on gene expression and signaling. As a result of these functions, one-carbon and polyamine metabolism have recently drawn a lot of interest for their part in cancer malignancy. Therapeutic inhibitors that target one-carbon and polyamine metabolism have thus been trialed as anticancer medications. The significance and future possibilities of one-carbon and polyamine metabolism as a target in cancer therapy are discussed in this review.
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Affiliation(s)
- Anowarul Islam
- College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide 5001, Australia
| | - Zeeshan Shaukat
- Clinical and Health Sciences, University of South Australia, Adelaide 5001, Australia
| | - Rashid Hussain
- Clinical and Health Sciences, University of South Australia, Adelaide 5001, Australia
| | - Stephen L. Gregory
- College of Medicine and Public Health, Flinders University, Adelaide 5042, Australia
- Correspondence: ; Tel.: +61-0466987583
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Davalos V, Esteller M. Cancer epigenetics in clinical practice. CA Cancer J Clin 2022. [PMID: 36512337 DOI: 10.3322/caac.21765] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/07/2022] [Accepted: 10/20/2022] [Indexed: 12/15/2022] Open
Abstract
Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer-specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation-based assays and epigenetic drugs already approved by the US Food and Drug Administration.
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Affiliation(s)
- Veronica Davalos
- Josep Carreras Leukaemia Research Institute, Badalona, Catalonia, Spain
| | - Manel Esteller
- Josep Carreras Leukaemia Research Institute, Badalona, Catalonia, Spain
- Centro de Investigacion Biomedica en Red Cancer, Madrid, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
- Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Catalonia, Spain
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The Future of Biomarkers in Veterinary Medicine: Emerging Approaches and Associated Challenges. Animals (Basel) 2022; 12:ani12172194. [PMID: 36077913 PMCID: PMC9454634 DOI: 10.3390/ani12172194] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/30/2022] Open
Abstract
Simple Summary In this review we seek to outline the role of new technologies in biomarker discovery, particularly within the veterinary field and with an emphasis on ‘omics’, as well as to examine why many biomarkers-despite much excitement-have not yet made it to clinical practice. Further we emphasise the critical need for close collaboration between clinicians, researchers and funding bodies and the need to set clear goals for biomarker requirements and realistic application in the clinical setting, ensuring that biomarker type, method of detection and clinical utility are compatible, and adequate funding, time and sample size are available for all phases of development. Abstract New biomarkers promise to transform veterinary practice through rapid diagnosis of diseases, effective monitoring of animal health and improved welfare and production efficiency. However, the road from biomarker discovery to translation is not always straightforward. This review focuses on molecular biomarkers under development in the veterinary field, introduces the emerging technological approaches transforming this space and the role of ‘omics platforms in novel biomarker discovery. The vast majority of veterinary biomarkers are at preliminary stages of development and not yet ready to be deployed into clinical translation. Hence, we examine the major challenges encountered in the process of biomarker development from discovery, through validation and translation to clinical practice, including the hurdles specific to veterinary practice and to each of the ‘omics platforms–transcriptomics, proteomics, lipidomics and metabolomics. Finally, recommendations are made for the planning and execution of biomarker studies with a view to assisting the success of novel biomarkers in reaching their full potential.
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Zarogoulidis P, Kosmidis CS, Hohenforst-Schmidt W, Matthaios D, Sapalidis K, Petridis D, Perdikouri EI, Courcoutsakis N, Hatzibougias D, Arnaoutoglou C, Freitag L, Ioannidis A, Huang H, Tolis C, Bai C, Turner JF. Radial-EBUS: CryoBiopsy Versus Conventional Biopsy: Time-Sample and C-Arm. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19063569. [PMID: 35329255 PMCID: PMC8955438 DOI: 10.3390/ijerph19063569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/14/2022] [Accepted: 03/10/2022] [Indexed: 12/21/2022]
Abstract
Introduction: Diagnosis of lung nodules is still under investigation. We use computed tomography scans and positron emission tomography in order to identify their origin. Patients and Methods: In our retrospective study, we included 248 patients with a single lung nodule or multiple lung nodules of size ≥1 cm. We used a radial-endobronchial ultrasound and a C-Arm. We used a 1.1 mm cryoprobe versus a 22G needle vs. forceps/brush. We compared the sample size of each biopsy method with the number of cell-block slices. Results: Central lesions indifferent to the method provided the same mean number of cell-block slices (0.04933–0.02410). Cryobiopsies provide less sample size for peripheral lesions due to the higher incidence of pneumothorax (0.04700–0.02296). Conclusion: The larger the lesion ≥2 cm, and central, more cell-blocks are produced indifferent to the biopsy method (0.13386–0.02939). The time of the procedure was observed to be less when the C-Arm was used as an additional navigation tool (0.14854–0.00089).
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Affiliation(s)
- Paul Zarogoulidis
- Pulmonary-Oncology Department, General Clinic Euromedica, Private Hospital, 54645 Thessaloniki, Greece
- Correspondence:
| | - Christoforos S. Kosmidis
- Surgical Department, University Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki (AUTH), 1st St. Kiriakidi Street, 54621 Thessaloniki, Greece; (C.S.K.); (K.S.)
| | - Wolfgang Hohenforst-Schmidt
- Sana Clinic Group Franken, Department of Cardiology/Pulmonology/Intensive Care/Nephrology, “Hof” Clinics, University of Erlangen, 91052 Hof, Germany;
| | - Dimitrios Matthaios
- Department of Medical Oncology, Rhodes General Hospital, 85133 Rhodes, Greece;
| | - Konstantinos Sapalidis
- Surgical Department, University Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki (AUTH), 1st St. Kiriakidi Street, 54621 Thessaloniki, Greece; (C.S.K.); (K.S.)
| | - Dimitrios Petridis
- Department of Food Science and Technology, International Hellenic University, 54621 Thessaloniki, Greece;
| | | | - Nikos Courcoutsakis
- Department of Radiology and Medical Imaging, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | | | - Christos Arnaoutoglou
- Department of Obstetrics & Gynecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece;
| | - Lutz Freitag
- Pulmonary Department, University Hospital of Zurich, 8004 Zurich, Switzerland;
| | - Aristeidis Ioannidis
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai 200001, China; (A.I.); (H.H.); (C.B.)
| | - Haidong Huang
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai 200001, China; (A.I.); (H.H.); (C.B.)
| | - Christos Tolis
- Oncoderm Private Oncology Clinic, 45221 Ioannina, Greece;
| | - Chong Bai
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai 200001, China; (A.I.); (H.H.); (C.B.)
| | - J. Francis Turner
- Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37001, USA;
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Zarogoulidis P, Kosmidis C, Kougkas N, Lallas A, Petridis D, Hohenforst-Schmidt W, Huang H, Freitag L, Sardeli C. Modification of Apremilast from Pills to Aerosol a Future Concept. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:11590. [PMID: 34770103 PMCID: PMC8582726 DOI: 10.3390/ijerph182111590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/22/2021] [Accepted: 11/01/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Inhaled drugs have been available in the market for several years and for several diseases. Drugs for chronic obstructive pulmonary disease, cystic fibrosis, and diabetes have been used for several years. In the field of drug modification, these drugs range from tablets to aerosol. METHODS Milling as used to break down the tablets to powder and nebulisers are used to produce aerosol droplets. A mastersizer was used to measure the mass median aerodynamic diameter of the aerosol droplets. RESULTS Apremilast produced mmad diameters (2.43 μm) without any statistical difference between the different jet-nebulizers. The residual cup B contributed to greater mmad diameters as the 95% interval of mean values, based on those the ANOVA mean square clearly indicated, followed by cups C and F. The previous interval plot is much better clarified when the interaction means between drug and residual cap are plotted. The residual cups B, C and F produce mmad between (2.0-3.2). CONCLUSION In the current research study we demonstrated our methodology to create apremilast powder and produce apremilast aerosol droplets with different nebulisers and residual cups.
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Affiliation(s)
- Paul Zarogoulidis
- Pulmonary Department, General Clinic, Euromedica Private Hospital, 546 45 Thessaloniki, Greece
- 3rd Surgery Department, AHEPA University General Hospital, Aristotle University of Thessaloniki, 546 21 Thessaloniki, Greece;
| | - Christoforos Kosmidis
- 3rd Surgery Department, AHEPA University General Hospital, Aristotle University of Thessaloniki, 546 21 Thessaloniki, Greece;
| | - Nikolaos Kougkas
- Rheumatology Department, IPPOKRATEIO University General Hospital, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece;
| | - Aimilios Lallas
- 1st Dermatology Department, Aristotle University of Thessaloniki, 540 06 Thessaloniki, Greece;
| | - Dimitris Petridis
- Department of Food Science and Technology, International Hellenic University, 507 01 Thessaloniki, Greece;
| | - Wolfgang Hohenforst-Schmidt
- Sana Clinic Group Franken, Department of Cardiology, Pulmonology, Intensive Care, Nephrology, Hof Clinics, University of Erlangen, 91054 Hof, Germany;
| | - Haidong Huang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Naval Medical University (Changhai Hospital, Second Military Medical University), Shanghai 200433, China;
| | - Lutz Freitag
- Department of Pulmonology, University Hospital Zurich, 8091 Zurich, Switzerland;
| | - Chrisanthi Sardeli
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 546 45 Thessaloniki, Greece;
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12
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Pilikidou M, Palyvou F, Papadopoulou SK, Tsiouda T, Tsekitsidi E, Arvaniti K, Miziou A, Tsingerlioti Z, Apostolidis G, Ntiloudis R, Boniou K, Tsioudas AA, Cheva A, Petridis D, Zarogoulidis P. Lung cancer, treatment and nutritional status. Mol Clin Oncol 2021; 15:248. [PMID: 34671467 DOI: 10.3892/mco.2021.2410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 09/24/2021] [Indexed: 01/29/2023] Open
Abstract
Lung cancer is often diagnosed at inoperable advanced stages, and most patients exhibit cancer cachexia. The nutritional status of patients has been previously observed to serve a key role in cancer survival and cancer surgery. The aim of the current study was to collect information regarding the treatment of patients and associate them with different nutritional measurements. A total of 82 patients with non-small cell lung cancer were included in the present study. Several parameters were assessed, such as body mass index (BMI), Mediterranian diet score, number of years spent smoking, basic metabolsim (RMR; kcal/day), VO2 (ml/min), ventilation (lt/min) and physical activity. All the aforementioned parameters were associated with patient treatment, nutritional status and survival. Two-way ANOVA was conducted and pairwise group mean differences were tested using Fisher's LSD and Tukey tests. Normality and variance homogeneity was checked in all cases. The results revealed that RMR and oxygen consumption were negatively affected by the survival status of patients (P=0.012 and P=0.043, respectively). The mean fat difference was higher in patients treated with immunotherapy, and lower in those treated with chemotherapy in addition to immunotherapy, as demonstrated by Tukey comparisons. The survival of 25 patients were affected by the treatment they received (P=0.006). Chemotherapy administered in addition to immunotherapy prolonged patient life almost two-fold when compared with the individual effects of the two treatments, which became equal according to Fisher's LSD comparisons. In conclusion, the nutritional status of patients was associated with the administration of chemotherapy in addition to immunotherapy, and patient survival. Increased metabolism and fat mass were also associated with prolonged survival.
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Affiliation(s)
- Maria Pilikidou
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 54623 Thessaloniki, Greece.,Pulmonary-Oncology Department, 'Theageneio' Cancer Hospital, 54007 Thessaloniki, Greece
| | - Foteini Palyvou
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 54623 Thessaloniki, Greece
| | - Sousana K Papadopoulou
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 54623 Thessaloniki, Greece
| | - Theodora Tsiouda
- Pulmonary-Oncology Department, 'Theageneio' Cancer Hospital, 54007 Thessaloniki, Greece
| | - Eirini Tsekitsidi
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 54623 Thessaloniki, Greece
| | - Konstantina Arvaniti
- Pulmonary-Oncology Department, 'Theageneio' Cancer Hospital, 54007 Thessaloniki, Greece
| | - Angeliki Miziou
- Pulmonary-Oncology Department, 'Theageneio' Cancer Hospital, 54007 Thessaloniki, Greece
| | - Zoi Tsingerlioti
- Pulmonary-Oncology Department, 'Theageneio' Cancer Hospital, 54007 Thessaloniki, Greece
| | - Georgios Apostolidis
- Pulmonary-Oncology Department, 'Theageneio' Cancer Hospital, 54007 Thessaloniki, Greece
| | - Romanos Ntiloudis
- Pulmonary-Oncology Department, 'Theageneio' Cancer Hospital, 54007 Thessaloniki, Greece
| | - Konstantina Boniou
- Pulmonary-Oncology Department, 'Theageneio' Cancer Hospital, 54007 Thessaloniki, Greece
| | - Athanasios A Tsioudas
- Department of Nutritional Sciences and Dietetics, Faculty of Health Sciences, International Hellenic University, 54623 Thessaloniki, Greece
| | - Angeliki Cheva
- Pathology Department, Faculty of Medicine, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece
| | - Dimitris Petridis
- Department of Food Science and Technology, School of Geosciences, International Hellenic University, 57400 Thessaloniki, Greece
| | - Paul Zarogoulidis
- Pulmonary Department, 'Bioclinic' Private Hospital, 54622 Thessaloniki, Greece
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13
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Zarogoulidis P, Petridis D, Huang H, Bai C, Hohenforst-Schmidt W, Freitag L, Baka S, Drougas D, Vagionas A, Tsakiridis K, Turner JF, Hatzibougias D, Boukovinas I, Zaric B, Kovacevic T, Ioannidis A, Courcoutsakis N, Matthaios D, Sardeli C. Biopsy and re-biopsy for PD-L1 expression in NSCLC. association between PD-L1 and checkpoint inhibitor efficacy through treatment in NSCLC. A pilot study. Expert Rev Respir Med 2021; 15:1483-1491. [PMID: 34591723 DOI: 10.1080/17476348.2021.1987888] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
INTRODUCTION Lung cancer is diagnosed at a late stage due to lack of early disease symptoms. Therefore an efficient treatment is necessary for prolonged disease free survival. PATIENTS AND METHODS In our study we recruited 124 patients NSCLC patients with adenocarcinoma and squamus cell carcinoma. All recuited patients had Programmed death-ligand 1 expression ≥50 (PD-L1)with DAKO technique. Immunotherapy was administered with as first line treatment. Re-biopsies were performed in the main lung lesion every 4 months with the restaging of the patient and also in the metastastic sites in other organs that occurred during treatment. PD-L1 expressed was evaluated in the biopsies of the metastatic sites. RESULTS It appears thereafter that the PD-L1 expression could easily be claimed as a promising bio-index with a cutoff value 65, below which a negative prognosis of the disease progress will be evident and above that value a positive continuation of the disease will be prominent. CONCLUSION The findings of this study suggest that the PD-L1-65 index works adequately either concerning the neo-metastatic sites or the patient disease responses. Re-biopsies in new metastastic sites are necessary since we probably have a new cancer and chemotherapy should be added. More studies should confirm are results and change the NSCLC treatment approach of these patients.
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Affiliation(s)
- Paul Zarogoulidis
- 3rd Department of Surgery, ``ahepa`` University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece.,Pulmonary Oncology Department, ``Bioclinic`` Private Hospital, Thessaloniki, Greece
| | - Dimitris Petridis
- Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, Thessaloniki, Greece
| | - Haidong Huang
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Chong Bai
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Wolfgang Hohenforst-Schmidt
- Sana Clinic Group Franken, Department of Cardiology/Pulmonology/Intensive Care/Nephrology, "Hof" Clinics, University of Erlangen, Hof, Germany
| | - Lutz Freitag
- Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland
| | - Sofia Baka
- Oncology Department, ``Interbalkan`` European Medical Center, Thessaloniki, Greece
| | - Dimitris Drougas
- Nuclear Medicine Department, ``Bioiatriki`` Private PET-CT Laboratory, Thessaloniki, Greece
| | | | - Kosmas Tsakiridis
- Thoracic Oncology Department, ``Interbalkan`` European Medical Center, Thessaloniki, Greece
| | - J Francis Turner
- Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, USA
| | - Dimitris Hatzibougias
- Pulmonary department, Private Pathology Laboratory, "Microdiagnostics", Thessaloniki, Greece
| | - Ioannis Boukovinas
- Oncology Department, ``Bioclinic`` Private Hospital, Thessaloniki, Greece
| | - Bojan Zaric
- Faculty of Medicine, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Novi Sad, Serbia
| | - Tomi Kovacevic
- Faculty of Medicine, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Novi Sad, Serbia
| | - Aris Ioannidis
- Surgery Department, ``genesis`` Private HJospital, Thessaloniki, Greece
| | - Nikolaos Courcoutsakis
- Radiology Department, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | | | - Chrisanthi Sardeli
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
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14
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Zarogoulidis P, Hatzibougias D, Tsakiridis K, Matthaios D, Hohenforst-Schmidt W, Huang H, Bai C, Tryfon S, Saroglou M, Zaric B, Boujkovinas I, Karapantzou C. Lymphadenopathy and granulomas: benignancy of malignancy and differential diagnosis with endobronchial ultrasound-transbronchial needle biopsy 19G needle fine-needle aspiration biopsy. Lung Cancer Manag 2021; 10:LMT49. [PMID: 34408790 PMCID: PMC8369527 DOI: 10.2217/lmt-2021-0002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/29/2021] [Indexed: 01/17/2023] Open
Abstract
Endobronchial ultrasound (EBUS) is a very useful tool for the diagnosis of lymphadenopathy of the mediastinum. Nowadays, EBUS can substitute video-assisted thoracic surgery when a 19G needle is used. Several studies have provided data for efficient diagnosis not only for lung cancer, but for also sarcoidosis, tuberculosis and lymphoma. We present five cases of EBUS-transbronchial needle biopsy 19G needle used for the diagnosis of mediastinum lymphadenopathy. We present not only the pathological diagnosis, but also the steps for the differential clinical and pathological differential diagnosis for sarcoidosis, tuberculosis, cancer metastasis, respiratory infection and lymphoma.
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Affiliation(s)
- Paul Zarogoulidis
- 3 University Surgery Department, AHEPA University General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.,Pulmonary Department, 'Bioclinic' Private Clinic, Thessaloniki, Greece
| | | | - Kosmas Tsakiridis
- Thoracic Surgery Department, 'Interbalkan' European Medical Center, Thessaloniki, Greece
| | | | - Wolfgang Hohenforst-Schmidt
- Department of Cardiology/Pulmonology/Intensive Care/Nephrology, Sana Clinic Group Franken, 'Hof' Clinics, University of Erlangen, Hof, Germany
| | - Haidong Huang
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, PR China
| | - Chong Bai
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, PR China
| | - Stavros Tryfon
- Pulmonary Department (NHS), 'G Papanikolaou' General Hospital, Thessaloniki, Greece
| | - Maria Saroglou
- Pulmonary Department (NHS), 'G Papanikolaou' General Hospital, Thessaloniki, Greece
| | - Bojan Zaric
- Faculty of Medicine, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Novi Sad, Serbia
| | | | - Chrisanthi Karapantzou
- Ear, Nose & Throat (ENT) Department, Ludwig-Maximilians University of Munich, Munich, Germany
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15
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Wu J, Li P. Detection of short stature homeobox 2 and RAS-associated domain family 1 subtype A DNA methylation in interventional pulmonology. World J Clin Cases 2021; 9:5391-5397. [PMID: 34307592 PMCID: PMC8281403 DOI: 10.12998/wjcc.v9.i20.5391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/07/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most important aspects of interventional pulmonology is to obtain tissue or liquid samples of the chest to diagnose a respiratory disease; however, it is still possible to obtain insufficient tissue or cytologic specimens. Indeed, methylation detection is an effective method by which to establish a diagnosis. This review focuses on the clinical application of short stature homeobox 2 and RAS-associated domain family 1 subtype A DNA methylation detection in interventional pulmonology, including bronchoscopic fluid biopsy, transbronchial needle aspiration, and pleural effusion.
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Affiliation(s)
- Jian Wu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Peng Li
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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16
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DNA methylation of PTGER4 in peripheral blood plasma helps to distinguish between lung cancer, benign pulmonary nodules and chronic obstructive pulmonary disease patients. Eur J Cancer 2021; 147:142-150. [PMID: 33662689 DOI: 10.1016/j.ejca.2021.01.032] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/23/2021] [Accepted: 01/28/2021] [Indexed: 12/13/2022]
Abstract
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.
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17
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Zarogoulidis P, Huang H, Zhou J, Ning Y, Yang M, Wang J, Zhang R, Bai C, Shen X, Huang Z, Petridis D, Kosmidis C, Kosmidou M, Tsakiridis K, Hohenforst-Schmidt W, Baka S, Petanidis S, Zaric B, Kovacevic T, Stojsic V, Sarcev T, Bursac D, Kukic B, Rapti A, Pantea S, Rogoveanu O, Rogoveanu I, Romanidis K, Kesisoglou I, Ioannidis A, Vagionas A, Sapalidis K. Thyroid cancer diagnosis with transdermal probe 22G U/S versus EBUS-convex probe TBNA-B 22G and 19G: pros and cons. Expert Rev Med Devices 2021; 18:197-201. [PMID: 33482695 DOI: 10.1080/17434440.2021.1880891] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Thyroid cancer is usually diagnosed both with imaging techniques and transdermal biopsy. Laboratory tests are also included in the initial work-up. PATIENTS AND METHODS One hundred and thirty patients were included in our study with pathological imaging findings in the thyroid region. Biopsies were performed with 22 G with transdermal convex probe, EBUS 22 G Mediglobe® needle and 19 G Olympus® needle. We investigated the efficiency and safety of both techniques and identified the best candidates for each method. DISCUSSION 19 G needle identified cancer types such as; Lymphoma, Medullary thyroid cancer, and Hurthle cell cancer, which we know from previous pathology studies that a larger sample is necessary for diagnosis. No safety issues were observed for both techniques and the EBUS technique produced more cell block material when 22 G needle was compared to transdermal biopsy in peritracheal lesions. CONCLUSION The method of biopsy should be made based on the size and accessibility of the lesion.
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Affiliation(s)
- Paul Zarogoulidis
- 3rdSurgery Department, Medical School of Health Sciences, ``AHEPA`` University Hospital, Thessaloniki, Greece
| | - Haidong Huang
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, P. R. China
| | - Jun Zhou
- Department of Respiratory, Changzhou maternal and child health care hospital affiliated to Nanjing Medical University, Changzhou, Jiangsu Changzhou, China
| | - Yunye Ning
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, P. R. China
| | - Meng Yang
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, P. R. China.,Department of Geriatrics, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Jiannan Wang
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, P. R. China
| | - Rong Zhang
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, P. R. China
| | - Chong Bai
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, P. R. China
| | - Xiaping Shen
- Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zhiang Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Henan University, Henan Kaifeng, China
| | - Dimitris Petridis
- Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, Thessaloniki, Greece
| | - Christoforos Kosmidis
- 3rdSurgery Department, Medical School of Health Sciences, ``AHEPA`` University Hospital, Thessaloniki, Greece
| | - Maria Kosmidou
- Internal Medicine Department, University of Ioannina, Ioannina, Greece
| | - Kosmas Tsakiridis
- Thoracic Surgery Department, ``Interbalkan`` European Medical Center, Thessaloniki, Greece
| | - Wolfgang Hohenforst-Schmidt
- Sana Clinic Group Franken, Department of Cardiology/Pulmonology/Intensive Care/Nephrology, "Hof" Clinics, University of Erlangen, Hof, Germany
| | - Sofia Baka
- Onc/ology Department, Interbalkan European Medical Center, Thessaloniki, Greece
| | - Savas Petanidis
- Department of Pulmonology, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Bojan Zaric
- Faculty of Medicine, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Novi Sad, Serbia
| | - Tomi Kovacevic
- Faculty of Medicine, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Novi Sad, Serbia
| | - Vladimir Stojsic
- Faculty of Medicine, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Novi Sad, Serbia
| | - Tatjana Sarcev
- Faculty of Medicine, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Novi Sad, Serbia
| | - Daliborka Bursac
- Faculty of Medicine, University of Novi Sad, Institute for Pulmonary Diseases of Vojvodina, Novi Sad, Serbia
| | - Biljana Kukic
- Faculty of Medicine, University of Novi Sad, Institute for Oncology of Vojvodina, Novi Sad, Serbia
| | - Aggeliki Rapti
- Pulmonary Oncology Department, ``sotiria`` Hospital of Chest Diseases, Athens, Greece
| | - Stelian Pantea
- 3rdSurgery Department, Medical School of Health Sciences, ``AHEPA`` University Hospital, Thessaloniki, Greece.,Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Henan University, Henan Kaifeng, China
| | - Otelia Rogoveanu
- Department of Medical Rehabilitation, University of Medicine and Pharmacy, Craiova, Romania
| | - Ion Rogoveanu
- Department of Medical Rehabilitation, University of Medicine and Pharmacy, Craiova, Romania
| | - Konstantinos Romanidis
- Second Department of Surgery, General University Hospital of Alexandroupolis, Medical School Democritus University of Thrace, Alexandroupolis, Greece
| | - Issak Kesisoglou
- 3rdSurgery Department, Medical School of Health Sciences, ``AHEPA`` University Hospital, Thessaloniki, Greece
| | - Aris Ioannidis
- Surgery Department, ``Genesis`` Private Hospital, Thessaloniki, Greece
| | | | - Konstantinos Sapalidis
- 3rdSurgery Department, Medical School of Health Sciences, ``AHEPA`` University Hospital, Thessaloniki, Greece
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18
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Shi J, Chen X, Zhang L, Fang X, Liu Y, Zhu X, Zhang H, Fan L, Gu J, Zhang S, She B, Han H, Yi X. Performance Evaluation of SHOX2 and RASSF1A Methylation for the Aid in Diagnosis of Lung Cancer Based on the Analysis of FFPE Specimen. Front Oncol 2020; 10:565780. [PMID: 33425721 PMCID: PMC7793934 DOI: 10.3389/fonc.2020.565780] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 11/09/2020] [Indexed: 12/28/2022] Open
Abstract
Emerging molecular diagnostic methods are more sensitive and objective, which can overcome the intrinsic failings of morphological diagnosis. Here, a RT-PCR-based in vitro diagnostic test kit (LungMe®) was developed and characterized to simultaneously quantify the DNA methylation of SHOX2 and RASSF1A in FFPE tissue specimens. The clinical manifestations were evaluated in 251 FFPE samples with specificity and sensitivity of 90.4 and 89.8%, respectively. Furthermore, the quantitative analysis shows that the degree of SHOX2 methylation was correlated with the stages of lung cancer, but not in the case of RASSF1A. Our observation indicated that the DNA methylation of SHOX2 and RASSF1A may play different roles in cancer development. Comparison of the methylation levels of SHOX2 and RASSF1A between cancer and cancer-adjacent specimens (n = 30), showed they have “epigenetic field defect”. As additional clinical validation, the hypermethylation of SHOX2 and RASSF1A was detected not only in surgical operative specimens, but also in histopathological negative puncture biopsies. SHOX2 and RASSF1A methylation detection can be used to increase sensitivity and NPV, which provide us with a more accurate method of differential diagnosis and are likely to be rapidly applied in clinical examinations.
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Affiliation(s)
- Juanhong Shi
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Xue Chen
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Long Zhang
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Xia Fang
- Department of Pulmonary and Critical Care Medicine, Dongfang Hospital Affiliated to Tongji University, Shanghai, China
| | - Yuting Liu
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Xuyou Zhu
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Haoyang Zhang
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Lichao Fan
- Department of Pulmonary and Critical Care Medicine, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, China
| | - Jun Gu
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Suxia Zhang
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Bin She
- Academic Development, Tellgen Corporation, Shanghai, China
| | - Hongxiu Han
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
| | - Xianghua Yi
- Department of Pathology, Tongji Hospital, Tongji University, Shianghai, China
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19
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Sardeli C, Zarogoulidis P, Romanidis K, Oikonomou P, Sapalidis K, Huang H, Bai C, Hohenforst-Schmidt W, Tsakiridis K, Zaric B, Perin B, Ioannidis A, Baka S, Drevelegas K, Kosmidou M, Kosmidis C. Acute pneumothorax due to immunotherapy administration in non-small cell lung cancer. Respir Med Case Rep 2020; 31:101258. [PMID: 33145157 PMCID: PMC7596337 DOI: 10.1016/j.rmcr.2020.101258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 10/08/2020] [Accepted: 10/11/2020] [Indexed: 11/10/2022] Open
Abstract
Nowadays we have novel therapies for advanced stage non-small cell lung cancer. Immunotherapy has been introduced in the market for several years and until now its administration is mostly based on the programmed death-ligand 1. First line treatment with immunotherapy can be administered alone if programmed death-ligand 1 expression is ≥ 50%. All therapies for advanced stage disease have advantages and disadvantages, immunotherapy until now has presented mild adverse effects when compared to chemotherapy. However; it is known to induce inflammatory response to different tissues within the body. In our case acute pneumothorax was induced after immunotherapy administration.
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Affiliation(s)
- Chrysanthi Sardeli
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paul Zarogoulidis
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.,3rd Department of Surgery, ''AHEPA'' University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Konstantinos Romanidis
- Second Department of Surgery, University Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Panagoula Oikonomou
- Second Department of Surgery, University Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos Sapalidis
- 3rd Department of Surgery, ''AHEPA'' University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Haidong Huang
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Chong Bai
- Department of Respiratory & Critical Care Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, China
| | - Wolfgang Hohenforst-Schmidt
- Sana Clinic Group Franken, Department of Cardiology / Pulmonology / Intensive Care / Nephrology, ''Hof'' Clinics, University of Erlangen, Hof, Germany
| | - Kosmas Tsakiridis
- Thoracic Surgery Department, ''Interbalkan'' European Medical Center, Thessaloniki, Greece
| | - Bojan Zaric
- Institute for Pulmonary Diseases of Vojvodina, Faculty of Medicine, University of Novi Sad, Serbia
| | - Branislav Perin
- Institute for Pulmonary Diseases of Vojvodina, Faculty of Medicine, University of Novi Sad, Serbia
| | - Aris Ioannidis
- Surgery Department, ''Genesis'' Private Hospital, Thessaloniki, Greece
| | - Sofia Baka
- Oncology Department, ''Intebalkan'' European Medical Center, Thessaloniki, Greece
| | | | - Maria Kosmidou
- Internal Medicine, University Hospital of Ioannina, Ioannina, Greece
| | - Christoforos Kosmidis
- 3rd Department of Surgery, ''AHEPA'' University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
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20
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Li N, Zeng Y, Huang J. Signaling pathways and clinical application of RASSF1A and SHOX2 in lung cancer. J Cancer Res Clin Oncol 2020; 146:1379-1393. [PMID: 32266538 DOI: 10.1007/s00432-020-03188-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/17/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND An increasing number of studies have focused on the early diagnostic value of the methylation of RASSF1A and SHOX2 in lung cancer. However, the intricate cellular events related to RASSF1A and SHOX2 in lung cancer are still a mystery. For researchers and clinicians aiming to more profoundly understand the diagnostic value of methylated RASSF1A and SHOX2 in lung cancer, this review will provide deeper insights into the molecular events of RASSF1A and SHOX2 in lung cancer. METHODOLOGY We searched for relevant publications in the PubMed and Google Scholar databases using the keywords "RASSF1A", "SHOX2" and "lung cancer" etc. First, we reviewed the RASSF1A and SHOX2 genes, from their family structures to the functions of their basic structural domains. Then we mainly focused on the roles of RASSF1A and SHOX2 in lung cancer, especially on their molecular events in recent decades. Finally, we compared the value of measuring RASSF1A and SHOX2 gene methylation with that of the common methods for the diagnosis of lung cancer patients. RESULTS The RASSF1A and SHOX2 genes were confirmed to be regulators or effectors of multiple cancer signaling pathways, driving tumorigenesis and lung cancer progression. The detection of RASSF1A and SHOX2 gene methylation has higher sensitivity and specificity than other commonly used methods for diagnosing lung cancer, especially in the early stage. CONCLUSIONS The RASSF1A and SHOX2 genes are critical for the processes of tumorigenesis, development, metastasis, drug resistance, and recurrence in lung cancer. The combined detection of RASSF1A and SHOX2 gene methylation was identified as an excellent method for the screening and surveillance of lung cancer that exhibits high sensitivity and specificity.
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Affiliation(s)
- Nanhong Li
- Department of Pathology, Guangdong Medical University, Zhanjiang, 524023, China
| | - Yu Zeng
- Department of Respiration, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524003, China
| | - Jian Huang
- Department of Pathology, Guangdong Medical University, Zhanjiang, 524023, China.
- Pathological Diagnosis and Research Center, Affiliated Hospital, Guangdong Medical University, Zhanjiang, 524001, China.
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21
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Xu Z, Wang Y, Wang L, Xiong J, Wang H, Cui F, Peng H. The performance of the SHOX2/ PTGER4 methylation assay is influenced by cancer stage, age, type and differentiation. Biomark Med 2020; 14:341-351. [PMID: 32250153 DOI: 10.2217/bmm-2019-0325] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Aim: To investigate the clinicopathological factors affecting the mSHOX2/mPTGER4 assay performance and its application in lung cancer detection in Chinese population. Materials & methods: A total of 455 subjects were recruited in this case-control study (302 untreated lung cancer patients, 153 normal subjects). Blood samples were collected before therapy and the mSHOX2/mPTGER4 level was measured with Epi proLung assay. Results: The mSHOX2/mPTGER4 sensitivity was 75.6% at 84.8% specificity. Both markers showed stage-dependent sensitivity. mSHOX2 was more sensitive to small-cell lung cancer and mPTGER4 was more sensitive to poorly differentiated lung cancer. Sensitivity increased with age but was not affected by sex. The mPRGER4/mSHOX2 sensitivity was significantly higher than that of protein markers. Conclusion: The mSHOX2/mPTGER4 assay showed some values with more limitations in lung cancer early detection.
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Affiliation(s)
- Zheyuan Xu
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.,Department of Thoracic Surgery, The Affiliated Hospital of Kunming University of Science & Technology, Kunming, Yunnan, China
| | - Yang Wang
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.,Department of Thoracic Surgery, The Affiliated Hospital of Kunming University of Science & Technology, Kunming, Yunnan, China
| | - Lan Wang
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.,Department of Thoracic Surgery, The Affiliated Hospital of Kunming University of Science & Technology, Kunming, Yunnan, China
| | - Jian Xiong
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.,Department of Thoracic Surgery, The Affiliated Hospital of Kunming University of Science & Technology, Kunming, Yunnan, China
| | - Han Wang
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.,Department of Thoracic Surgery, The Affiliated Hospital of Kunming University of Science & Technology, Kunming, Yunnan, China
| | - Fengxian Cui
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.,Department of Thoracic Surgery, The Affiliated Hospital of Kunming University of Science & Technology, Kunming, Yunnan, China
| | - Hao Peng
- Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China.,Department of Thoracic Surgery, The Affiliated Hospital of Kunming University of Science & Technology, Kunming, Yunnan, China
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22
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Sardeli C, Zarogoulidis P, Kosmidis C, Amaniti A, Katsaounis A, Giannakidis D, Koulouris C, Hohenforst-Schmidt W, Huang H, Bai C, Michalopoulos N, Tsakiridis K, Romanidis K, Oikonomou P, Mponiou K, Vagionas A, Goganau AM, Kesisoglou I, Sapalidis K. Inhaled chemotherapy adverse effects: mechanisms and protection methods. Lung Cancer Manag 2020; 8:LMT19. [PMID: 31983927 PMCID: PMC6978726 DOI: 10.2217/lmt-2019-0007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Lung cancer is still diagnosed at a late stage due to a lack of symptoms. Although there are novel therapies, many patients are still treated with chemotherapy. In an effort to reduce adverse effects associated with chemotherapy, inhaled administration of platinum analogs has been investigated. Inhaled administration is used as a local route in order to reduce the systemic adverse effects; however, this treatment modality has its own adverse effects. In this mini review, we present drugs that were administered as nebulized droplets or dry powder aerosols for non-small-cell lung cancer. We present the adverse effects and methods to overcome them.
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Affiliation(s)
- Chrysanthi Sardeli
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paul Zarogoulidis
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.,Third Department of Surgery, 'AHEPA' University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Christoforos Kosmidis
- Third Department of Surgery, 'AHEPA' University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Aikaterini Amaniti
- Anesthesiology Department, 'AHEPA' University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Athanasios Katsaounis
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Giannakidis
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Charilaos Koulouris
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Wolfgang Hohenforst-Schmidt
- Sana Clinic Group Franken, Department of Cardiology/Pulmonology/Intensive Care/Nephrology, 'Hof' Clinics, University of Erlangen, Hof, Germany
| | - Haidong Huang
- The Diagnostic & Therapeutic Center of Respiratory Diseases, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Chong Bai
- The Diagnostic & Therapeutic Center of Respiratory Diseases, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Nikolaos Michalopoulos
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kosmas Tsakiridis
- Thoracic Surgery Department, 'Interbalkan' European Medical Center, Thessaloniki, Greece
| | - Konstantinos Romanidis
- Second Department of Surgery, University Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Panagoula Oikonomou
- Second Department of Surgery, University Hospital of Alexandroupolis, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantina Mponiou
- Radiotherapy Department, 'Theageneio' Anti-Cancer Hospital, Thessaloniki, Greece
| | | | - Alexandru Marian Goganau
- General Surgery Clinic 1, University of Medicine and Pharmacy of Craiova, Craiova County Emergency Hospital, Craiova, Romania
| | - Isaak Kesisoglou
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Sapalidis
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
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23
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Zang R, Wang X, Jin R, Lei Y, Huang J, Liu C, Zheng S, Zhou F, Wu Q, Sun N, Gao S, He J. Translational value of IDH1 and DNA methylation biomarkers in diagnosing lung cancers: a novel diagnostic panel of stage and histology-specificity. J Transl Med 2019; 17:430. [PMID: 31888670 PMCID: PMC6936123 DOI: 10.1186/s12967-019-2117-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 10/26/2019] [Indexed: 12/24/2022] Open
Abstract
Background Lung cancer is the leading cause of cancer-related death worldwide, and the timely and serial assessment of low-dose computed tomography (LDCT) in high-risk populations remains a challenge. Furthermore, testing a single biomarker for the diagnosis of lung cancers is of relatively low effectiveness. Thus, a stronger diagnostic combination of blood biomarkers is needed to improve the diagnosis of non-small cell lung cancer (NSCLC). Methods The blood levels of individual biomarkers [IDH1, DNA methylation of short stature homeobox 2 gene (SHOX2), and prostaglandin E receptor 4 gene (PTGER4)] were measured and statistically analyzed in samples from healthy controls and patients with lung cancer. In total, 221 candidates were enrolled and randomly assigned into two groups for the training and validation of a diagnostic panel. Additionally, a subgroup analysis was performed in the whole cohort. Results A newly combined 3-marker diagnostic model for lung cancers was established and validated with area under the receiver operating characteristic (ROC) curve (AUC) values ranging from 0.835 to 0.905 in independent groups showing significantly stronger diagnostic value compared with a single tested biomarker. The sensitivity of the diagnostic model was as high as 86.1% and 80.0% in the training and validation sets, respectively. Although no apparent differences were found between the 3-marker and 2-marker models, the high clinical T-stage and histological type specificity of IDH1 and two other methylated DNA biomarkers were demonstrated in the subgroup analysis. Conclusions The combination of single biomarkers with high stage-specificity and histological type specificity (SHOX2 and PTGER4 DNA methylation and IDH1) showed better diagnostic performance in the detection of lung cancers compared with single marker assessment. A greater clinical utility of the panel may be developed by adding demographic/epidemiologic characteristics.
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Affiliation(s)
- Ruochuan Zang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xinfeng Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Runsen Jin
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yuanyuan Lei
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jianbing Huang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chengming Liu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Sufei Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fang Zhou
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qian Wu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Nan Sun
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Asai A, Konno M, Koseki J, Taniguchi M, Vecchione A, Ishii H. One-carbon metabolism for cancer diagnostic and therapeutic approaches. Cancer Lett 2019; 470:141-148. [PMID: 31759958 DOI: 10.1016/j.canlet.2019.11.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/08/2019] [Accepted: 11/18/2019] [Indexed: 12/31/2022]
Abstract
Altered metabolism is critical for the rapid and unregulated proliferation of cancer cells; hence the requirement for an abundant source of nucleotides. One characteristic of this metabolic reprogramming is in one-carbon (1C) metabolism, which is particularly noteworthy for its role in DNA synthesis. Various forms of methylation are also noteworthy as they relate to cancer cell survival and proliferation. In recent years, 1C metabolism has received substantial attention for its role in cancer malignancy via these functions. Therefore, therapeutic inhibitors targeting 1C metabolism have been utilized as anticancer drugs. This review outlines the importance of 1C metabolism and its clinical application in cancer. Understanding 1C metabolism could aid the development of novel cancer diagnostic and therapeutic methods.
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Affiliation(s)
- Ayumu Asai
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan; Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan; Artificial Intelligence Research Center, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, 567-0047, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan
| | - Jun Koseki
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan
| | - Masateru Taniguchi
- Artificial Intelligence Research Center, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, 567-0047, Japan
| | - Andrea Vecchione
- Department of Clinical and Molecular Medicine, University of Rome "Sapienza", Santo Andrea Hospital, Via di Grottarossa, Rome, 1035-00189, Italy
| | - Hideshi Ishii
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan.
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25
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Ibrahim J, Op de Beeck K, Fransen E, Peeters M, Van Camp G. The Gasdermin E Gene Has Potential as a Pan-Cancer Biomarker, While Discriminating between Different Tumor Types. Cancers (Basel) 2019; 11:cancers11111810. [PMID: 31752152 PMCID: PMC6896019 DOI: 10.3390/cancers11111810] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 01/08/2023] Open
Abstract
Due to the elevated rates of incidence and mortality of cancer, early and accurate detection is crucial for achieving optimal treatment. Molecular biomarkers remain important screening and detection tools, especially in light of novel blood-based assays. DNA methylation in cancer has been linked to tumorigenesis, but its value as a biomarker has not been fully explored. In this study, we have investigated the methylation patterns of the Gasdermin E gene across 14 different tumor types using The Cancer Genome Atlas (TCGA) methylation data (N = 6502). We were able to identify six CpG sites that could effectively distinguish tumors from normal samples in a pan-cancer setting (AUC = 0.86). This combination of pan-cancer biomarkers was validated in six independent datasets (AUC = 0.84–0.97). Moreover, we tested 74,613 different combinations of six CpG probes, where we identified tumor-specific signatures that could differentiate one tumor type versus all the others (AUC = 0.79–0.98). In all, methylation patterns exhibited great variation between cancer and normal tissues, but were also tumor specific. Our analyses highlight that a Gasdermin E methylation biomarker assay, not only has the potential for being a methylation-specific pan-cancer detection marker, but it also possesses the capacity to discriminate between different types of tumors.
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Affiliation(s)
- Joe Ibrahim
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; (J.I.); (K.O.d.B.); (E.F.)
- Centre for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium;
| | - Ken Op de Beeck
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; (J.I.); (K.O.d.B.); (E.F.)
- Centre for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium;
| | - Erik Fransen
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; (J.I.); (K.O.d.B.); (E.F.)
- StatUa Centre for Statistics, University of Antwerp, 2000 Antwerp, Belgium
| | - Marc Peeters
- Centre for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium;
- Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
| | - Guy Van Camp
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Edegem, Belgium; (J.I.); (K.O.d.B.); (E.F.)
- Centre for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium;
- Correspondence: ; Tel.: +32-3275-9762
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26
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Leiro-Fernandez V, De Chiara L, Rodríguez-Girondo M, Botana-Rial M, Valverde D, Núñez-Delgado M, Fernández-Villar A. Methylation Assessment for the Prediction of Malignancy in Mediastinal Adenopathies Obtained by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Patients with Lung Cancer. Cancers (Basel) 2019; 11:cancers11101408. [PMID: 31547177 PMCID: PMC6826358 DOI: 10.3390/cancers11101408] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/13/2019] [Accepted: 09/18/2019] [Indexed: 12/11/2022] Open
Abstract
The evaluation of mediastinal lymph nodes is critical for the correct staging of patients with lung cancer (LC). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique for mediastinal staging, though unfortunately lymph node micrometastasis is often missed by cytological analysis. The aim of this study was to evaluate the predictive capacity of methylation biomarkers and provide a classification rule for predicting malignancy in false negative EBUS-TBNA samples. The study included 112 patients with a new or suspected diagnosis of LC that were referred to EBUS-TBNA. Methylation of p16/INK4a, MGMT, SHOX2, E-cadherin, DLEC1, and RASSF1A was quantified by nested methylation-specific qPCR in 218 EBUS-TBNA lymph node samples. Cross-validated linear regression models were evaluated to predict malignancy. According to EBUS-TBNA and final diagnosis, 90 samples were true positives for malignancy, 110 were true negatives, and 18 were false negatives. MGMT, SHOX2, and E-cadherin were the methylation markers that better predicted malignancy. The model including sex, age, short axis diameter and standard uptake value of adenopathy, and SHOX2 showed 82.7% cross-validated sensitivity and 82.4% specificity for the detection of malignant lymphadenopathies among negative cytology samples. Our results suggest that the predictive model approach proposed can complement EBUS-TBNA for mediastinal staging.
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Affiliation(s)
- Virginia Leiro-Fernandez
- Pulmonary Department, Hospital Álvaro Cunqueiro, Vigo Health Area, 36312 Vigo, Spain; (M.B.-R.); (M.N.-D.); (A.F.-V.)
- NeumoVigoI+i Research Group, Vigo Biomedical Research Institute (IBIV), 36312 Vigo, Spain
- Correspondence: (L.D.C.); (V.L.-F.)
| | - Loretta De Chiara
- Department of Biochemistry, Genetics and Immunology, Biomedical Research Center (CINBIO), University of Vigo, 36310 Vigo, Spain;
- Correspondence: (L.D.C.); (V.L.-F.)
| | - Mar Rodríguez-Girondo
- Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
- SiDOR Research Group, Biomedical Research Center (CINBIO), University of Vigo, 36310 Vigo, Spain
| | - Maribel Botana-Rial
- Pulmonary Department, Hospital Álvaro Cunqueiro, Vigo Health Area, 36312 Vigo, Spain; (M.B.-R.); (M.N.-D.); (A.F.-V.)
- NeumoVigoI+i Research Group, Vigo Biomedical Research Institute (IBIV), 36312 Vigo, Spain
| | - Diana Valverde
- Department of Biochemistry, Genetics and Immunology, Biomedical Research Center (CINBIO), University of Vigo, 36310 Vigo, Spain;
| | - Manuel Núñez-Delgado
- Pulmonary Department, Hospital Álvaro Cunqueiro, Vigo Health Area, 36312 Vigo, Spain; (M.B.-R.); (M.N.-D.); (A.F.-V.)
- NeumoVigoI+i Research Group, Vigo Biomedical Research Institute (IBIV), 36312 Vigo, Spain
| | - Alberto Fernández-Villar
- Pulmonary Department, Hospital Álvaro Cunqueiro, Vigo Health Area, 36312 Vigo, Spain; (M.B.-R.); (M.N.-D.); (A.F.-V.)
- NeumoVigoI+i Research Group, Vigo Biomedical Research Institute (IBIV), 36312 Vigo, Spain
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27
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Lan VTT, Trang VL, Ngan NT, Son HV, Toan NL. An Internal Control for Evaluating Bisulfite Conversion in the Analysis of Short Stature Homeobox 2 Methylation in Lung Cancer. Asian Pac J Cancer Prev 2019; 20:2435-2443. [PMID: 31450918 PMCID: PMC6852808 DOI: 10.31557/apjcp.2019.20.8.2435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 08/01/2019] [Indexed: 12/17/2022] Open
Abstract
Objective: The methylation status is considered as powerful diagnostic, prognostic, and predictive biomarkers. However, the limited DNA amount and conversion efficiency after bisulfite treatment are considerable hindrances in quantitative methylation analysis. In this study, we designed an artificial internal control (IC) system that contained the cytosine-free fragment (CFF) following CpG sequences of the SHOX2 promoter whose methylation status has been described as a valuable biomarker of lung cancer. Its performance in quantifying DNA recovery and bisulfite conversion efficiency as well as in detecting false-positive SHOX2 methylation was determined on samples from lung cancer patients. Material and Methods: The IC system is composed of two pConIC and pUnIC plasmids that both contain a cytosine-free (CF) sequence derived from the CFF and the CpG containing SHOX2 sequences. They are identical in sequence, except that in the ConIC insert, all cytosines have been converted into thymines. Thus, the ConIC can be used as calibrator of 100% bisulfite conversion efficiency, while the UnIC is the indicator in order to evaluate the DNA recovery, bisulfite conversion efficiency of the SHOX2 promoter sequence by quantitative real time PCR. Results: The copy number of the target sequences impacted on both DNA recovery rates and bisulfite conversion efficiency. An amount of 0.005 ng pUnIC (106 copies) showed recovery rate of 18%, similar to that of pConIC, and a bisulfite conversion efficiency of the SHOX2 reaching 98.7%. On the contrary, higher copy number of pUnIC showed incomplete conversion (<85%) and over recovery (~42%). Using this calibrator/indicator couple, we were able to detect false-positive SHOX2 methylation (3.77% instead of 0.03%) due to incomplete bisulfite conversion.Conclusion: Our results proposed a customizable internal control using the ConIC/UnIC as calibrator/indicator to quantify simultaneously and accurately the DNA recovery and bisulfite conversion efficiencies of individual sequence as well as whole genome in methylation assays, thus promoting the validation of standardized clinical DNA methylation biomarker values to progress toward clinical applications
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Affiliation(s)
| | - Vu Lan Trang
- Sorbonne Universités, UPMC Univ. Paris 06, École normale supérieure, PSL Research University, CNRS, INSERM, APHP, Laboratoire des Biomolécules (LBM), Paris, France
| | | | | | - Nguyen Linh Toan
- Department of Pathophysiology, Medical University, Ha Dong, Vietnam
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Belanger AR, Hollyfield J, Yacovone G, Ceppe AS, Akulian JA, Burks AC, Rivera MP, Dodd LG, Long JM, Haithcock BE, Pecot CV. Incidence and clinical relevance of non-small cell lung cancer lymph node micro-metastasis detected by staging endobronchial ultrasound-guided transbronchial needle aspiration. J Thorac Dis 2019; 11:3650-3658. [PMID: 31559073 DOI: 10.21037/jtd.2019.05.36] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Approximately twenty percent of lymph node (LN) negative non-small cell lung cancer (NSCLC) patients who undergo curative intent surgery have pan-cytokeratin immunohistochemistry (IHC)-detectable occult micro-metastases (MMs) in resected LNs. The presence of the MMs in NSCLC is associated worsened outcomes. As a substantial proportion of NSCLC LN staging is conducted using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), we sought to determine the frequency of detection of occult MMs in EBUS-TBNA specimens and to evaluate the impact of MMs on progression-free and overall survival. Methods We performed retrospective IHC staining for pan-cytokeratin of EBUS-TBNA specimens previously deemed negative by a cytopathologist based on conventional hematoxylin and eosin staining. The results were correlated with clinical variables, including survival outcomes. Results Of 887 patients screened, 44 patients were identified meeting inclusion criteria with sufficient additional tissue for testing. With respect to the time of the EBUS-TBNA procedure, 52% of patients were clinical stage I, 34% clinical stage II, and clinical 14% stage IIIa NSCLC. Three patients (6.8%) were found to have cytokeratin positive MMs. All 3 MMs detected were at N2 LN stations. The presence of MMs was associated with significantly decreased progression-free (median 210 vs. 1,293 days, P=0.0093) and overall survival (median 239 vs. 1,120 days, P=0.0357). Conclusions Occult LN MMs can be detected in EBUS-TBNA specimens obtained during staging examinations and are associated with poor clinical outcomes. If prospectively confirmed, these results have significant implications for EBUS-TBNA specimen analyses and possibly for the NSCLC staging paradigm.
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Affiliation(s)
- Adam R Belanger
- Section of Interventional Pulmonology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Johnathan Hollyfield
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Gabriella Yacovone
- Lineberger Comprehensive Cancer Center, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Agathe S Ceppe
- Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Jason A Akulian
- Section of Interventional Pulmonology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - A Cole Burks
- Section of Interventional Pulmonology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - M Patricia Rivera
- Section of Interventional Pulmonology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Leslie G Dodd
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Jason M Long
- Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina, Chapel Hill, NC, USA
| | - Benjamin E Haithcock
- Division of Cardiothoracic Surgery, Department of Surgery, University of North Carolina, Chapel Hill, NC, USA
| | - Chad V Pecot
- Lineberger Comprehensive Cancer Center, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
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Peng X, Liu X, Xu L, Li Y, Wang H, Song L, Xiao W. The mSHOX2 is capable of assessing the therapeutic effect and predicting the prognosis of stage IV lung cancer. J Thorac Dis 2019; 11:2458-2469. [PMID: 31372283 PMCID: PMC6626805 DOI: 10.21037/jtd.2019.05.81] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 05/16/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Instant monitoring of the therapeutic effect of systematic therapy in late-stage lung cancer is crucial for response assessment and strategy adjustment. Previous study found that specific plasma methylation markers may be applied to therapeutic effect assessment. In order to investigate the performance of plasma mSHOX2 in assessing the therapeutic effect and predicting the prognosis of stage IV lung cancer, we performed the study focusing on patients underwent chemotherapy or tyrosine kinase inhibitor (TKI)-based targeted therapy. METHODS Blood samples from 163 subjects, including 30 stage I, 29 stage II, 26 stage III and 68 stage IV lung cancer patients, were recruited in this study. Quantitative relationship between primary tumor size and the plasma mSHOX2 level was established. Blood samples before therapy and two cycles after therapy were obtained from 68 stage IV patients, and the mSHOX2 level was quantified as ΔΔCt. RESULTS Sharp decrease of plasma mSHOX2 level was seen in patients with partial response (PR) while not in those with stable disease (SD). The plasma mSHOX2 level change reflected the degree of response and correlated with the maximal diameter of primary tumors in linear relationship. The mSHOX2 levels before and two cycles after therapy were predictors of the overall survival, while the mSHOX2 level change or the tumor size change were not predictors of the overall survival. Furthermore, univariable and multivariable Cox regression revealed that mSHOX2 level before therapy was the only independent predictor of the overall survival with a hazard ratio of 1.414. CONCLUSIONS mSHOX2 is effective for therapeutic effect assessment and prognosis prediction of stage IV lung cancer patients underwent systematic therapy.
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Affiliation(s)
- Xiumei Peng
- The Chinese PLA Medical College and the Chinese PLA General Hospital, Beijing 100853, China
- Department of Oncology, the Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100037, China
| | - Xiaoliang Liu
- Department of Radiotherapy, the Chinese PLA General Hospital, Beijing 100853, China
| | - Long Xu
- Department of Oncology, the General Hospital of the Chinese PLA Northern Theater Command, Shenyang 110016, China
| | - Yuemin Li
- The Chinese PLA Medical College and the Chinese PLA General Hospital, Beijing 100853, China
- Department of Radiotherapy, the Eighth Medical Center of the Chinese PLA General Hospital, Beijing 100091, China
| | - Huaiqing Wang
- Department of Radiotherapy, the Eighth Medical Center of the Chinese PLA General Hospital, Beijing 100091, China
- Department of Graduate, Hebei North University, Zhangjiakou 075000, China
| | - Lele Song
- The Chinese PLA Medical College and the Chinese PLA General Hospital, Beijing 100853, China
- Department of Radiotherapy, the Eighth Medical Center of the Chinese PLA General Hospital, Beijing 100091, China
- BioChain (Beijing) Science and Technology, Inc., Beijing 100176, China
| | - Wenhua Xiao
- The Chinese PLA Medical College and the Chinese PLA General Hospital, Beijing 100853, China
- Department of Oncology, the Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100037, China
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Kosmidis C, Sapalidis K, Zarogoulidis P, Sardeli C, Koulouris C, Giannakidis D, Pavlidis E, Katsaounis A, Michalopoulos N, Mantalobas S, Koimtzis G, Alexandrou V, Tsiouda T, Amaniti A, Kesisoglou I. Inhaled Cisplatin for NSCLC: Facts and Results. Int J Mol Sci 2019; 20:ijms20082005. [PMID: 31022839 PMCID: PMC6514814 DOI: 10.3390/ijms20082005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/15/2019] [Accepted: 04/18/2019] [Indexed: 12/20/2022] Open
Abstract
Although we have new diagnostic tools for non-small cell lung cancer, diagnosis is still made in advanced stages of the disease. However, novel treatments are being introduced in the market and new ones are being developed. Targeted therapies and immunotherapy have brought about a bloom in the treatment of non-small cell lung cancer. Still we have to find ways to administer drugs in a more efficient and safe method. In the current review, we will focus on the administration of inhaled cisplatin based on published data.
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Affiliation(s)
- Christoforos Kosmidis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Konstantinos Sapalidis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Paul Zarogoulidis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 57001 Thessaloniki, Greece.
| | - Chrysanthi Sardeli
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 57001 Thessaloniki, Greece.
| | - Charilaos Koulouris
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Dimitrios Giannakidis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Efstathios Pavlidis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Athanasios Katsaounis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Nikolaos Michalopoulos
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Stylianos Mantalobas
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Georgios Koimtzis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Vyron Alexandrou
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Theodora Tsiouda
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Aikaterini Amaniti
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
| | - Issak Kesisoglou
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, 57001 Thessaloniki, Greece.
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Inage T, Nakajima T, Itoga S, Ishige T, Fujiwara T, Sakairi Y, Wada H, Suzuki H, Iwata T, Chiyo M, Yoshida S, Matsushita K, Yasufuku K, Yoshino I. Molecular Nodal Staging Using miRNA Expression in Lung Cancer Patients by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration. Respiration 2018; 96:267-274. [PMID: 29898461 DOI: 10.1159/000489178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 04/06/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The limited negative predictive value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has often been discussed. OBJECTIVE The aim of this study was to identify a highly sensitive molecular biomarker for lymph node staging by EBUS-TBNA. METHODS Five microRNAs (miRNAs) (miR-200a, miR-200b, miR-200c, miR-141, and let-7e) were selected as biomarker candidates for the detection of nodal metastasis in a miRNA expression analysis. After having established a cutoff level of expression for each marker to differentiate malignant from benign lymph nodes among surgically dissected lymph nodes, the cutoff level was applied to snap-frozen EBUS-TBNA samples. Archived formalin-fixed paraffin- embedded (FFPE) samples rebiopsied by EBUS-TBNA after induction chemoradiotherapy were also analyzed. RESULTS The expression of all candidate miRNAs was significantly higher in metastatic lymph nodes than in benign ones (p < 0.05) among the surgical samples. miR-200c showed the highest diagnostic yield, with a sensitivity of 95.4% and a specificity of 100%. When the cutoff value for miR-200c was applied to the snap-frozen EBUS-TBNA samples, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 97.4, 81.8, 95.0, 90.0, and 94.0%, respectively. For restaging FFPE EBUS- TBNA samples, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 100, 60.0, 80.0, 100, and 84.6%, respectively. Among the restaged samples, 4 malignant lymph nodes were false negative by EBUS-TBNA, but they were accurately identified by miR-200c. CONCLUSIONS miR-200c can be used as a highly sensitive molecular staging biomarker that will enhance nodal staging of lung cancer.
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Affiliation(s)
- Terunaga Inage
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takahiro Nakajima
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Sakae Itoga
- Clinical Laboratory, Chiba University Hospital, Chiba, Japan
| | - Takayuki Ishige
- Clinical Laboratory, Chiba University Hospital, Chiba, Japan
| | - Taiki Fujiwara
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuichi Sakairi
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hironobu Wada
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hidemi Suzuki
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takekazu Iwata
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masako Chiyo
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shigetoshi Yoshida
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kazuyuki Matsushita
- Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kazuhiro Yasufuku
- Division of Thoracic Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Ichiro Yoshino
- Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
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Sapalidis K, Zarogoulidis P, Pavlidis E, Laskou S, Katsaounis A, Koulouris C, Giannakidis D, Mantalovas S, Huang H, Bai C, Wen Y, Wang L, Sardeli C, Amaniti A, Karapantzos I, Karapantzou C, Hohenforst-Schmidt W, Konstantinou F, Kesisoglou I, Benhanseen N. Aerosol Immunotherapy with or without Cisplatin for metastatic lung cancer non-small cell lung cancer disease: In vivo Study. A more efficient combination. J Cancer 2018; 9:1973-1977. [PMID: 29896282 PMCID: PMC5995940 DOI: 10.7150/jca.24782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 03/07/2018] [Indexed: 12/30/2022] Open
Abstract
Lung cancer is the leading cause of cancer death after prostate cancer for males and breast cancer for females. There are novel therapies in the past five years such as; tyrosine kinase inhibitors and most recently in the last two years immunotherapy. Immunotherapy is currently being investigated if it can be administered alone or in combination. Previously we have investigated whether immunotherapy compounds can be produced as aerosols, and in the current study we investigated the safety and efficiency independently of the programmed death-ligand 1. The aerosol administration of both cisplatin and nivolumab is possible. The combination of the two drugs has a synergistic effect and therefore should be considered an option. Time of administration for immunotherapy is also very important.
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Affiliation(s)
- Konstantinos Sapalidis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Paul Zarogoulidis
- Pulmonary Department-Oncology Unit, "Theageneio" Cancer Hospital, Thessaloniki, Greece
| | - Efstathios Pavlidis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Stella Laskou
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Athanasios Katsaounis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Charilaos Koulouris
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Dimitrios Giannakidis
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Stylianos Mantalovas
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Haidong Huang
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Chong Bai
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yuting Wen
- Department of Respiratory Diseases, The Affiliated Jiangning hospital of Nanjing Medical University, Nanjing, China
| | - Li Wang
- Department of Respiratory Diseases, The Affiliated Jiangning hospital of Nanjing Medical University, Nanjing, China
| | - Chrysanthi Sardeli
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aikaterini Amaniti
- Anesthesiology Department, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Ilias Karapantzos
- Ear, Nose and Throat Department, "Saint Luke" Private Hospital, Panorama, Thessaloniki, Greece
| | - Chrysanthi Karapantzou
- Ear, Nose and Throat Department, "Saint Luke" Private Hospital, Panorama, Thessaloniki, Greece
| | - Wolfgang Hohenforst-Schmidt
- Sana Clinic Group Franken, Department of Cardiology / Pulmonology / Intensive Care / Nephrology, ''Hof'' Clinics, University of Erlangen, Hof, Germany
| | - Fotis Konstantinou
- Thoracic Surgery Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Isaak Kesisoglou
- 3rd Department of Surgery, "AHEPA" University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Naim Benhanseen
- Sana Clinic Group Franken, Department of Cardiology / Pulmonology / Intensive Care / Nephrology, ''Hof'' Clinics, University of Erlangen, Hof, Germany
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Absmaier M, Napieralski R, Schuster T, Aubele M, Walch A, Magdolen V, Dorn J, Gross E, Harbeck N, Noske A, Kiechle M, Schmitt M. PITX2 DNA-methylation predicts response to anthracycline-based adjuvant chemotherapy in triple-negative breast cancer patients. Int J Oncol 2018; 52:755-767. [PMID: 29328369 PMCID: PMC5807037 DOI: 10.3892/ijo.2018.4241] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 10/19/2017] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) constitutes a heterogeneous breast cancer subgroup with poor prognosis; survival rates are likely to be lower with TNBC compared to other breast cancer subgroups. For this disease, systemic adjuvant chemotherapy regimens often yield suboptimal clinical results. To improve treatment regimens in TNBC, identification of molecular biomarkers may help to select patients for individualized adjuvant therapy. Evidence has accumulated that determination of the methylation status of the PITX2 gene provides a predictive value in various breast cancer subgroups, either treated with endocrine-based therapy or anthracycline-containing chemotherapy. To further explore the validity of this novel predictive candidate biomarker, in the present exploratory retrospective study, determination of the PITX2 DNA-methylation status was assessed for non-metastatic TNBC patients treated with adjuvant anthracycline-based chemotherapy by molecular analysis of breast cancer tissues. The PITX2 DNA-methylation status was determined in fresh-frozen tumor tissue specimens (n=56) by methylation-specific qRT-PCR (qMSP) and the data related to disease-free and overall survival, applying an optimized DNA-methylation score of 6.35%. For non-metastatic TNBC patients treated with adjuvant systemic anthracycline-based chemotherapy, a low PITX2 DNA-methylation status (<6.35) defines TNBC patients with poor disease-free and overall survival. Univariate and multivariate analyses demonstrate the statistically independent predictive value of PITX2 DNA-methylation. For non-metastatic TNBC patients, selective determination of the PITX2 DNA-methylation status may serve as a cancer biomarker for predicting response to anthracycline-based adjuvant chemotherapy. The assay based on methylation of the PIXT2 gene can be applied to frozen and routinely available formalin-fixed, paraffin-embedded (FFPE) breast cancer tumor tissues that will not only define those TNBC patients who may benefit from anthracycline-based chemotherapy but also those who should be spared the necessity of such potentially toxic treatment. Such patients should be allocated to alternative treatment options.
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Affiliation(s)
- Magdalena Absmaier
- Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany
| | - Rudolf Napieralski
- Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany
| | - Tibor Schuster
- Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany
| | - Michaela Aubele
- Institute of Pathology, Helmholtz Zentrum Muenchen, Neuherberg, Germany
| | - Axel Walch
- Institute of Pathology, Helmholtz Zentrum Muenchen, Neuherberg, Germany
| | - Viktor Magdolen
- Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany
| | - Julia Dorn
- Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany
| | - Eva Gross
- Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany
| | - Nadia Harbeck
- Breast Center, Klinikum der Ludwig Maximilians Universität München, Munich, Germany
| | - Aurelia Noske
- Department of Pathology and Pathological Anatomy, Technische Universität München, Munich, Germany
| | - Marion Kiechle
- Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany
| | - Manfred Schmitt
- Department of Obstetrics and Gynecology, Technische Universität München, Munich, Germany
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Pan Y, Liu G, Zhou F, Su B, Li Y. DNA methylation profiles in cancer diagnosis and therapeutics. Clin Exp Med 2018; 18:1-14. [PMID: 28752221 DOI: 10.1007/s10238-017-0467-0] [Citation(s) in RCA: 267] [Impact Index Per Article: 38.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 06/16/2017] [Indexed: 12/12/2022]
Abstract
Cancer initiation and proliferation is regulated by both epigenetic and genetic events with epigenetic modifications being increasingly identified as important targets for cancer research. DNA methylation catalyzed by DNA methyltransferases (DNMTs) is one of the essential epigenetic mechanisms that control cell proliferation, apoptosis, differentiation, cell cycle, and transformation in eukaryotes. Recent progress in epigenetics revealed a deeper understanding of the mechanisms of tumorigenesis and provided biomarkers for early detection, diagnosis, and prognosis in cancer patients. Although DNA methylation biomarker possesses potential contributing to precision medicine, there are still limitations to be overcome before it reaches clinical setting. Hence, the current status of DNA methylation biomarkers was reviewed and the future use in clinic was also predicted.
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Affiliation(s)
- Yunbao Pan
- Department of Laboratory Medicine, Zhongnan Hospital, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China
| | - Guohong Liu
- School of Materials Science and Engineering, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 6767 Bertner Ave, Houston, TX, 77030, USA
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Bojin Su
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 6767 Bertner Ave, Houston, TX, 77030, USA.
| | - Yirong Li
- Department of Laboratory Medicine, Zhongnan Hospital, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.
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Zhang C, Yu W, Wang L, Zhao M, Guo Q, Lv S, Hu X, Lou J. DNA Methylation Analysis of the SHOX2 and RASSF1A Panel in Bronchoalveolar Lavage Fluid for Lung Cancer Diagnosis. J Cancer 2017; 8:3585-3591. [PMID: 29151944 PMCID: PMC5687174 DOI: 10.7150/jca.21368] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 08/28/2017] [Indexed: 12/22/2022] Open
Abstract
Introduction: Currently the majority of lung cancer patients are diagnosed as advanced diseases for no sensitive and specific biomarkers exist, noninvasive biomarkers with high sensitivity and specificity are urgently needed in lung cancer diagnosis. Bronchoscopy is a standard procedure of the diagnostic work-up of patients with suspected lung cancer despite of the limited diagnostic accuracy. Besides, epigenetic changes through DNA methylation play an important role in tumorigenesis. Thus, we examined the aberrant methylation of the SHOX2 and RASSF1A in bronchoalveolar lavage fluid (BALF) in comparing with conventional cytology examination and serum CEA in order to evaluate the new diagnostic method. Patients and Methods: BALF and serum samples were collected from 322 patients at the time of diagnosis, 284 of them were pathologically confirmed lung cancer, 35 were benign lung diseases and 3 were malignancies in other systems. For all of the 322 patients, the methylation status of the SHOX2 and RASSF1A gene were detected by a new RT-PCR platform and then confirmed by sanger sequencing. Serum CEA were detected using electrochemiluminescence immunoassay. Results: Profiling data showed the consistency of RT-PCR and sanger sequencing in detecting the methylation of the SHOX2 and RASSF1A. Besides, the combination of SHOX2 and RASSF1A methylation in BALF yielded a diagnostic sensitivity of 81.0% and specificity of 97.4%. When compared with established cytology examination (sensitivity: 68.3%, specificity: 97.4%) and serum biomarker carcinoembryonic antigen (CEA) (sensitivity: 30.6%, specificity: 100.0%), the SHOX2 and RASSF1A methylation panel showed the highest diagnostic efficiency. Notably, the combination of cytology and the SHOX2 and RASSF1A methylation panel could significantly improve the diagnostic efficacy. Conclusion: The methylation analysis of the SHOX2 and RASSF1A panel in BALF with RT-PCR achieved a satisfactory sensitivity and specificity in lung cancer diagnosis, especially in an early stage. It could be used as a promising noninvasive biomarker for auxiliary diagnosis of lung cancer.
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Affiliation(s)
- Chenzi Zhang
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Wenjun Yu
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Lin Wang
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Mingna Zhao
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Qiaomei Guo
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Shaogang Lv
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Xiaomeng Hu
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Jiatao Lou
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
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Methylation analysis of SHOX2 and RASSF1A in bronchoalveolar lavage fluid for early lung cancer diagnosis. Ann Diagn Pathol 2017; 27:57-61. [PMID: 28325362 DOI: 10.1016/j.anndiagpath.2017.01.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 12/28/2016] [Accepted: 01/20/2017] [Indexed: 12/20/2022]
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Branchi V, Schaefer P, Semaan A, Kania A, Lingohr P, Kalff JC, Schäfer N, Kristiansen G, Dietrich D, Matthaei H. Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract. Clin Epigenetics 2016; 8:133. [PMID: 27999621 PMCID: PMC5153824 DOI: 10.1186/s13148-016-0299-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 11/29/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Biliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC. METHODS Relative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival. RESULTS SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865-0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631-0.873). CONCLUSIONS SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.
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Affiliation(s)
- V Branchi
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - P Schaefer
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - A Semaan
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - A Kania
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - P Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - J C Kalff
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - N Schäfer
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
| | - G Kristiansen
- Institute of Pathology, University Hospital Bonn, Bonn, Germany
| | - D Dietrich
- Institute of Pathology, University Hospital Bonn, Bonn, Germany.,Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany
| | - H Matthaei
- Department of General, Visceral, Thoracic and Vascular Surgery University Hospital Bonn, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
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Semaan A, van Ellen A, Meller S, Bergheim D, Branchi V, Lingohr P, Goltz D, Kalff JC, Kristiansen G, Matthaei H, Pantelis D, Dietrich D. SEPT9 and SHOX2 DNA methylation status and its utility in the diagnosis of colonic adenomas and colorectal adenocarcinomas. Clin Epigenetics 2016; 8:100. [PMID: 27660666 PMCID: PMC5028994 DOI: 10.1186/s13148-016-0267-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 09/13/2016] [Indexed: 02/06/2023] Open
Abstract
Background Colorectal cancer (CRC) appear to arise from precursor lesions in a well-characterized adenoma-carcinoma sequence. Significant efforts have been invested to develop biomarkers that identify early adenocarcinomas and adenomas with high-grade dysplasia, since these are believed to harbor a particularly high risk for malignant transition and thus require resection. Promoter methylation of SEPT9 and SHOX2 has been suggested as a biomarker for various solid malignant tumors. Hence, the present study aimed to test their biomarker potential in CRC and precursor lesions. Results Assessment of promoter methylation of SEPT9 distinguished adenomas and CRC from controls as well as advanced from non-advanced adenomas (all p < 0.001). Correspondingly, SHOX2 methylation levels in adenomas and colorectal carcinomas were significantly higher compared to those in normal control tissues (p < 0.001). Histologic transition from adenomas to CRC was paralleled by amplification of the SEPT9 gene locus. Conclusions SEPT9/SHOX2 methylation assays may help to distinguish colorectal cancer and adenomas from normal and inflammatory colonic tissue, as well as advanced from non-advanced adenomas. Further studies need to validate these findings before introduction in clinical routine.
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Affiliation(s)
- Alexander Semaan
- Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Anne van Ellen
- Institute of Pathology, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Sebastian Meller
- Institute of Pathology, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Dominik Bergheim
- Institute of Pathology, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Vittorio Branchi
- Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Philipp Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Diane Goltz
- Institute of Pathology, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Jörg C Kalff
- Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Glen Kristiansen
- Institute of Pathology, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Hanno Matthaei
- Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Dimitrios Pantelis
- Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Dimo Dietrich
- Institute of Pathology, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
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Weiss G, Schlegel A, Kottwitz D, König T, Tetzner R. Validation of the SHOX2/PTGER4 DNA Methylation Marker Panel for Plasma-Based Discrimination between Patients with Malignant and Nonmalignant Lung Disease. J Thorac Oncol 2016; 12:77-84. [PMID: 27544059 PMCID: PMC5226366 DOI: 10.1016/j.jtho.2016.08.123] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 07/15/2016] [Accepted: 08/09/2016] [Indexed: 12/17/2022]
Abstract
Introduction Low-dose computed tomography (LDCT) is used for screening for lung cancer (LC) in high-risk patients in the United States. The definition of high risk and the impact of frequent false-positive results of low-dose computed tomography remains a challenge. DNA methylation biomarkers are valuable noninvasive diagnostic tools for cancer detection. This study reports on the evaluation of methylation markers in plasma DNA for LC detection and discrimination of malignant from nonmalignant lung disease. Methods Circulating DNA was extracted from 3.5-mL plasma samples, treated with bisulfite using a commercially available kit, purified, and assayed by real-time polymerase chain reaction for assessment of DNA methylation of short stature homeobox 2 gene (SHOX2), prostaglandin E receptor 4 gene (PTGER4), and forkhead box L2 gene (FOXL2). In three independent case-control studies these assays were evaluated and optimized. The resultant assay, a triplex polymerase chain reaction combining SHOX2, PTGER4, and the reference gene actin, beta gene (ACTB), was validated using plasma from patients with and without malignant disease. Results A panel of SHOX2 and PTGER4 provided promising results in three independent case-control studies examining a total of 330 plasma specimens (area under the receiver operating characteristic curve = 91%–98%). A validation study with 172 patient samples demonstrated significant discriminatory performance in distinguishing patients with LC from subjects without malignancy (area under the curve = 0.88). At a fixed specificity of 90%, sensitivity for LC was 67%; at a fixed sensitivity of 90%, specificity was 73%. Conclusions Measurement of SHOX2 and PTGER4 methylation in plasma DNA allowed detection of LC and differentiation of nonmalignant diseases. Development of a diagnostic test based on this panel may provide clinical utility in combination with current imaging techniques to improve LC risk stratification.
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Triple-layer dissection of the lung adenocarcinoma transcriptome: regulation at the gene, transcript, and exon levels. Oncotarget 2016; 6:28755-73. [PMID: 26356813 PMCID: PMC4745690 DOI: 10.18632/oncotarget.4810] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 08/21/2015] [Indexed: 12/30/2022] Open
Abstract
Lung adenocarcinoma is one of the most deadly human diseases. However, the molecular mechanisms underlying this disease, particularly RNA splicing, have remained underexplored. Here, we report a triple-level (gene-, transcript-, and exon-level) analysis of lung adenocarcinoma transcriptomes from 77 paired tumor and normal tissues, as well as an analysis pipeline to overcome genetic variability for accurate differentiation between tumor and normal tissues. We report three major results. First, more than 5,000 differentially expressed transcripts/exonic regions occur repeatedly in lung adenocarcinoma patients. These transcripts/exonic regions are enriched in nicotine metabolism and ribosomal functions in addition to the pathways enriched for differentially expressed genes (cell cycle, extracellular matrix receptor interaction, and axon guidance). Second, classification models based on rationally selected transcripts or exonic regions can reach accuracies of 0.93 to 1.00 in differentiating tumor from normal tissues. Of the 28 selected exonic regions, 26 regions correspond to alternative exons located in such regulators as tumor suppressor (GDF10), signal receptor (LYVE1), vascular-specific regulator (RASIP1), ubiquitination mediator (RNF5), and transcriptional repressor (TRIM27). Third, classification systems based on 13 to 14 differentially expressed genes yield accuracies near 100%. Genes selected by both detection methods include C16orf59, DAP3, ETV4, GABARAPL1, PPAR, RADIL, RSPO1, SERTM1, SRPK1, ST6GALNAC6, and TNXB. Our findings imply a multilayered lung adenocarcinoma regulome in which transcript-/exon-level regulation may be dissociated from gene-level regulation. Our described method may be used to identify potentially important genes/transcripts/exonic regions for the tumorigenesis of lung adenocarcinoma and to construct accurate tumor vs. normal classification systems for this disease.
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Oezkan F, Khan AM, Hager T, Freitag L, Christoph D, Darwiche K. OSNA: A Fast Molecular Test Based on CK19 mRNA Concentration for Assessment of EBUS-TBNA Samples in Lung Cancer Patients. Clin Lung Cancer 2016; 17:198-204. [DOI: 10.1016/j.cllc.2015.09.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 09/03/2015] [Accepted: 09/11/2015] [Indexed: 01/06/2023]
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Zhao QT, Guo T, Wang HE, Zhang XP, Zhang H, Wang ZK, Yuan Z, Duan GC. Diagnostic value of SHOX2 DNA methylation in lung cancer: a meta-analysis. Onco Targets Ther 2015; 8:3433-9. [PMID: 26640383 PMCID: PMC4657794 DOI: 10.2147/ott.s94300] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
The diagnostic value of SHOX2 DNA methylation in patients with lung cancer remains controversial. Thus, we performed a systematic review and meta-analysis to assess diagnostic accuracy of SHOX2 DNA methylation in the lymph node, bronchial aspirates, pleural effusion, plasma, and tumor tissue for lung cancer. We conducted a comprehensive literature search in PubMed, Ovid, the Cochrane library, and Web of Science databases in May 2015. The diagnostic sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve were pooled using STATA 12.0 software. A total of 2,296 subjects included 1,129 lung cancer patients in eight studies were recruited in this meta-analysis. The summary estimates for SHOX2 DNA methylation in the diagnosis of lung cancer in these studies were pooled SEN =0.70 (95% confidence interval [CI]: 0.46–0.87), SPE =0.96 (95% CI: 0.91–0.99), PLR 20.01 (95% CI: 6.96–57.52), NLR 0.31 (95% CI: 0.15–0.64), and DOR 65.11 (95% CI: 13.10–323.61), and the area under the curve (AUC) was 0.96 (95% CI: 0.94–0.97). SHOX2 DNA methylation has greater diagnostic value in detecting lung cancer. In addition, considering the potential publication bias and high heterogeneity, further research studies with more well-designed and large sample sizes are needed in the future.
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Affiliation(s)
- Qing-Tao Zhao
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China
| | - Tao Guo
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China
| | - Hui-En Wang
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China
| | - Xiao-Peng Zhang
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China
| | - Hua Zhang
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China
| | - Zhi-Kang Wang
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China
| | - Zheng Yuan
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China
| | - Guo-Chen Duan
- Department of Thoracic Surgery, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China
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Assessment of methylation status of locoregional lymph nodes in lung cancer using EBUS-NA. Clin Exp Metastasis 2015; 32:637-46. [DOI: 10.1007/s10585-015-9733-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 06/22/2015] [Indexed: 12/30/2022]
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Abstract
Lung cancer is the most prevalent cancer in the world. Few effective and cheap methods are available so far for early detection and screening of lung cancer. Although histological and cytological examinations are gold standards in lung cancer diagnosis, patients are always at late stages when diagnosis is confirmed. Therefore, new diagnostic methods are needed urgently to increase the early diagnostic rate, enhance the confirmed diagnostic rate, and reduce mortality. The SHOX2 gene methylation assay has become a promising option for the above purposes. It has been shown to enhance the confirmed diagnostic rate of lung cancer in several clinical trials when combined with histological or cytological assays, and has the potential to become an early diagnostic tool. This article reviews the outcome of clinical trials using the SHOX2 gene methylation assay alone or in combination with other examinations, and suggests its future applications and research directions.
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Affiliation(s)
- Lele Song
- The Chinese PLA 309 Hospital, No. 17, Heishanhu Road, HaiDian District, Beijing, 100091, People's Republic of China,
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45
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Schmidt B, Beyer J, Dietrich D, Bork I, Liebenberg V, Fleischhacker M. Quantification of cell-free mSHOX2 Plasma DNA for therapy monitoring in advanced stage non-small cell (NSCLC) and small-cell lung cancer (SCLC) patients. PLoS One 2015; 10:e0118195. [PMID: 25675432 PMCID: PMC4326280 DOI: 10.1371/journal.pone.0118195] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 01/06/2015] [Indexed: 11/19/2022] Open
Abstract
Purpose Most patients suffering from advanced lung cancer die within a few months. To exploit new therapy regimens we need better methods for the assessment of a therapy response. Material and Methods In a pilot study we prospectively enrolled 36 patients with advanced NSCLC and SCLC (34 stage IV, 2 stage IIIB) of whom 34 received standard platinum-based chemo/radiotherapy and two were treated with a tyrosine kinase inhibitor. We measured the levels of extracellular methylated SHOX2 DNA (mSHOX2) in plasma before and during therapy until re-staging. The mSHOX2 analysis was blinded with respect to the clinical data making it an observational study. Results According to the re-staging of 31 first-line patients, 19 patients were classified as non-responders while 12 patients were in the responder group. We observed a tight correlation between radiological data and the change of plasma mSHOX2 level as the equivalent for a therapy response. A ROC analysis showed a high discriminatory power for both patient groups already one week after therapy start (AUC 0.844). Additionally, a Kaplan-Meier and Cox Proportional Hazards analyses revealed a strong relationship between survival and plasma mSHOX2 value p≤0.001 (hazard ratio 11.08) providing some evidence for mSHOX2 also being a predictive marker. Conclusion The longitudinal measurement of extracellular plasma mSHOX2 DNA yields information about the response to cytotoxic treatment and allows an early assessment of treatment response for lung cancer patients. If confirmed in a larger study this would be a valuable tool for selecting and guiding a cytotoxic treatment.
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Affiliation(s)
- Bernd Schmidt
- Clinic for Internal Medicine I, Department of Pneumology, UKH, Halle/Saale, Germany
| | - Julia Beyer
- Clinic for Internal Medicine I, Department of Pneumology, UKH, Halle/Saale, Germany
| | - Dimo Dietrich
- University Hospital Bonn, Institute of Pathology, Bonn, Germany
| | - Ines Bork
- Clinic for Internal Medicine I, Department of Pneumology, UKH, Halle/Saale, Germany
| | | | - Michael Fleischhacker
- Clinic for Internal Medicine I, Department of Pneumology, UKH, Halle/Saale, Germany
- * E-mail:
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Vaidya PJ, Kate AH, Yasufuku K, Chhajed PN. Endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer diagnosis and staging. Expert Rev Respir Med 2014; 9:45-53. [PMID: 25496515 DOI: 10.1586/17476348.2015.992784] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Lung cancer is one of the most prevalent types of cancer in the world. A complete diagnosis of lung cancer involves tissue acquisition for pathological subtype, molecular diagnosis and accurate staging of the disease to guide appropriate therapy. Real-time endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is minimally invasive and relatively safe procedure, which can be done on an outpatient basis under moderate sedation. EBUS-TBNA has been shown to be a safe modality to obtain tissue for diagnosis, staging and molecular profiling in lung cancer. EBUS-TBNA stands out in comparison with other modalities for tissue acquisition in lung cancer. EBUS-TBNA performed with the patient under moderate sedation yields sufficient tissue for sequential molecular analysis in most patients. In this review, we describe the role of EBUS-TBNA in various aspects of diagnosis and staging of lung cancer in the present era along with its future aspects.
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Affiliation(s)
- Preyas J Vaidya
- Institute of Pulmonology, Medical Research and Development, Mumbai, India
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Oezkan F, Khan A, Zarogoulidis P, Hohenforst-Schmidt W, Theegarten D, Yasufuku K, Nakajima T, Freitag L, Darwiche K. Efficient utilization of EBUS-TBNA samples for both diagnosis and molecular analyses. Onco Targets Ther 2014; 7:2061-5. [PMID: 25419143 PMCID: PMC4234164 DOI: 10.2147/ott.s72974] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND The assessment of an increasing number of molecular markers is becoming a standard requirement from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens. However, it is unclear how many needle passes should be performed and the amount of lung cancer cells that should be sent for molecular analyses. The objective of this study was to determine if it is feasible to divide the material obtained by EBUS-TBNA to allow for molecular analysis without compromising the accuracy of mediastinal staging. OBJECTIVE We aimed to determine if dividing EBUS-TBNA specimens has a negative impact on either histopathological diagnosis or molecular analysis. METHODS EBUS-TBNA was performed in 249 enlarged lymph nodes. Negative or ambiguous histopathological results were confirmed by surgical means and clinical follow-up over 6 months. The tissue obtained by EBUS-TBNA was placed onto a glass slide and divided for histopathological workup and molecular analysis. The number of passes was recorded. Both the accuracy of the mediastinal lymph node staging and the applicability of the sample division for molecular analysis were assessed. RESULTS Each lymph node was punctured an average of 3.18 times and division of the obtained material for diagnosis and molecular analysis was feasible in all cases. The sensitivity and accuracy of the mediastinal lymph node staging were 96.6% and 97.6%, respectively. A cytokeratin (CK)-19-mRNA concentration-based molecular test was feasible in 74.1% of cases. CONCLUSION Dividing EBUS-TBNA samples for both histopathological diagnosis and molecular testing is feasible and does not compromise the accuracy of mediastinal staging. This method may be an alternative to taking additional needle passes for molecular analyses.
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Affiliation(s)
- F Oezkan
- Department of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Am Khan
- Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - P Zarogoulidis
- Pulmonary Department-Oncology Unit, 'G Papanikolaou' General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - D Theegarten
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - K Yasufuku
- Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - T Nakajima
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - L Freitag
- Department of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - K Darwiche
- Department of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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DNA methylation biomarkers: cancer and beyond. Genes (Basel) 2014; 5:821-64. [PMID: 25229548 PMCID: PMC4198933 DOI: 10.3390/genes5030821] [Citation(s) in RCA: 190] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 08/17/2014] [Accepted: 09/01/2014] [Indexed: 12/23/2022] Open
Abstract
Biomarkers are naturally-occurring characteristics by which a particular pathological process or disease can be identified or monitored. They can reflect past environmental exposures, predict disease onset or course, or determine a patient's response to therapy. Epigenetic changes are such characteristics, with most epigenetic biomarkers discovered to date based on the epigenetic mark of DNA methylation. Many tissue types are suitable for the discovery of DNA methylation biomarkers including cell-based samples such as blood and tumor material and cell-free DNA samples such as plasma. DNA methylation biomarkers with diagnostic, prognostic and predictive power are already in clinical trials or in a clinical setting for cancer. Outside cancer, strong evidence that complex disease originates in early life is opening up exciting new avenues for the detection of DNA methylation biomarkers for adverse early life environment and for estimation of future disease risk. However, there are a number of limitations to overcome before such biomarkers reach the clinic. Nevertheless, DNA methylation biomarkers have great potential to contribute to personalized medicine throughout life. We review the current state of play for DNA methylation biomarkers, discuss the barriers that must be crossed on the way to implementation in a clinical setting, and predict their future use for human disease.
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49
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Dueñas-Gonzalez A, Alatorre B, Gonzalez-Fierro A. The impact of DNA methylation technologies on drug toxicology. Expert Opin Drug Metab Toxicol 2014; 10:637-646. [PMID: 24660662 DOI: 10.1517/17425255.2014.889682] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Drug toxicology is central to drug development. Despite improvements in our understanding of molecular and cell biology, high attrition rates in drug development continue, speaking to the difficulties of developing unequivocal methods to predict the efficacy and safety of drugs. AREAS COVERED In this review, the authors provide a short overview of the 'omics' technologies that have been applied to drug toxicology, with an emphasis on a whole-genome DNA methylation analysis. Preliminary results from DNA methylation analysis technologies that may help in predicting response and efficacy of a drug are discussed. EXPERT OPINION Currently, we cannot fully contextualize the application of epigenetics to the field of drug toxicology, as there are still many challenges to overcome before DNA methylation-based biomarkers can be effectively used in drug development. Comprehensive whole-genome DNA methylation methods for a unbiased analysis based on either microarray or next-generation sequencing need to be evaluated in drug toxicology in an intensive and systematic manner. Additionally, robust analysis systems need to be developed to decode the large amounts of data generated by whole-genome DNA methylation analyses as well as protocol standardization for reproducibility to develop meaningful databases that can be applied to drug toxicology.
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Affiliation(s)
- Alfonso Dueñas-Gonzalez
- Universidad Nacional Autonoma de Mexico UNAM/Instituto Nacional de Cancerologia, Unidad de Investigacion Biomedica en Cancer, Insituto de Investigaciones Biomedicas , San Fernando 22, Tlalpan, Mexico City , Mexico
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50
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Performance evaluation of kits for bisulfite-conversion of DNA from tissues, cell lines, FFPE tissues, aspirates, lavages, effusions, plasma, serum, and urine. PLoS One 2014; 9:e93933. [PMID: 24699908 PMCID: PMC3974851 DOI: 10.1371/journal.pone.0093933] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 03/08/2014] [Indexed: 12/31/2022] Open
Abstract
DNA methylation analyses usually require a preceding bisulfite conversion of the DNA. The choice of an appropriate kit for a specific application should be based on the specific performance requirements with regard to the respective sample material. In this study, the performance of nine kits was evaluated: EpiTect Fast FFPE Bisulfite Kit, EpiTect Bisulfite Kit, EpiTect Fast DNA Bisulfite Kit (Qiagen), EZ DNA Methylation-Gold Kit, EZ DNA Methylation-Direct Kit, EZ DNA Methylation-Lightning Kit (Zymo Research), innuCONVERT Bisulfite All-In-One Kit, innuCONVERT Bisulfite Basic Kit, innuCONVERT Bisulfite Body Fluids Kit (Analytik Jena). The kit performance was compared with regard to DNA yield, DNA degradation, DNA purity, conversion efficiency, stability and handling using qPCR, UV, clone sequencing, HPLC, and agarose gel electrophoresis. All kits yielded highly pure DNA suitable for PCR analyses without PCR inhibition. Significantly higher yields were obtained when using the EZ DNA Methylation-Gold Kit and the innuCONVERT Bisulfite kits. Conversion efficiency ranged from 98.7% (EpiTect Bisulfite Kit) to 99.9% (EZ DNA Methylation-Direct Kit). The inappropriate conversion of methylated cytosines to thymines varied between 0.9% (innuCONVERT Bisulfite kits) and 2.7% (EZ DNA Methylation-Direct Kit). Time-to-result ranged from 131 min (innuCONVERT kits) to 402 min (EpiTect Bisulfite Kit). Hands-on-time was between 66 min (EZ DNA Methylation-Lightning Kit) and 104 min (EpiTect Fast FFPE and Fast DNA Bisulfite kits). Highest yields from formalin-fixed and paraffin-embedded (FFPE) tissue sections without prior extraction were obtained using the innuCONVERT Bisulfite All-In-One Kit while the EZ DNA Methylation-Direct Kit yielded DNA with only low PCR-amplifiability. The innuCONVERT Bisulfite All-In-One Kit exhibited the highest versatility regarding different input sample materials (extracted DNA, tissue, FFPE tissue, cell lines, urine sediment, and cellular fractions of bronchial aspirates, pleural effusions, ascites). The innuCONVERT Bisulfite Body Fluids Kit allowed for the analysis of 3 ml plasma, serum, ascites, pleural effusions and urine.
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