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Momenimovahed Z, Mazidimoradi A, Allahqoli L, Salehiniya H. The Role of CA-125 in the Management of Ovarian Cancer: A Systematic Review. Cancer Rep (Hoboken) 2025; 8:e70142. [PMID: 40067023 PMCID: PMC11894717 DOI: 10.1002/cnr2.70142] [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: 10/11/2024] [Revised: 01/15/2025] [Accepted: 01/29/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND Ovarian cancer is frequently occurring and fatal for women. CA-125 is important in the screening, diagnosis, and treatment of ovarian cancer. This review study was conducted to explore the influence of CA-125 in addressing ovarian cancer. METHODS To investigate the role of CA-125 in ovarian cancer, we conducted a comprehensive search for high-quality articles in the Medline, Web of Science Core Collection and Scopus databases using the keywords "ovarian cancer," "ovarian carcinoma," "ovarian neoplasms," and "CA-125" from the 2000 to 2024. We included full-text, peer-reviewed articles in English with relevant keywords published since 2000. We excluded case reports, commentaries, letters to the editor, books, case series, systematic reviews, animal studies, and articles that were not accessible in full text. RESULTS After screening the 7947 records, 88 studies were included in this review. In the literature review, it was found that researchers utilized CA-125 for diagnosing ovarian cancer, its predicting, evaluating treatment response, assessing ovarian cancer survival, and early detection of recurrence. In some cases, researchers employed additional tumor markers alongside CA-125 to enhance the test's sensitivity. CONCLUSION CA-125 has become a pivotal marker for ovarian cancer. Its role in the diagnosis, treatment, and ongoing assessment of ovarian cancer cannot be overstated. Continuous monitoring of CA-125 levels can provide comprehensive insights, and categorizing patients as low-risk or high-risk based on CA-125 levels could lead to better outcomes. Integrating CA-125 with other biomarkers may enhance the accuracy of the test and elevate its relevance in patient care.
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Affiliation(s)
| | | | - Leila Allahqoli
- Midwifery DepartmentMinistry of Health and Medical EducationTehranIran
| | - Hamid Salehiniya
- Department of Epidemiology and Biostatistics, School of Health, Social Determinants of Health Research CenterBirjand University of Medical SciencesBirjandIran
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Song Q, Li Y, Wu T, Hu W, Liu Y, Liu A. Feasibility of iodine concentration parameter and extracellular volume fraction derived from dual-energy CT for distinguishing type I and type II epithelial ovarian carcinoma. Abdom Radiol (NY) 2024:10.1007/s00261-024-04752-4. [PMID: 39665991 DOI: 10.1007/s00261-024-04752-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 12/13/2024]
Abstract
OBJECTIVES To investigate the feasibility of using the iodine concentration (IC) parameter and extracellular volume (ECV) fraction derived from dual-energy CT for distinguishing between type I and type II epithelial ovarian carcinoma (EOC). METHODS This study retrospectively included 172 patients with EOC preoperatively underwent dual-energy CT scans. Patients were grouped as type I and type II EOC according to postoperatively pathologic results. Normalized IC (NIC, %) values from arterial-phase (AP), venous-phase (VP) and delay-phase (DP) were measured by two observers. ECV fraction (%) was calculated by DP-NIC and hematocrit. Intra-observer correlation coefficient (ICC) was used to assess the agreement between measurements made by two observers. The differences of imaging parameters between the two groups were compared. Logistic regression was used to select independent predictive factors and establish combined parameter. Receiver operating characteristic curve was used to analyze performance of all parameters. RESULTS The ICCs for all parameters exceeded 0.75. All parameters in type II EOC were all significantly higher than those in type I EOC (all P < 0.05). VP-NIC exhibited the highest Area under the curve (AUC) of 0.804, along with 80.39% sensitivity and 71.43% specificity. VP-NIC was identified as the independent factor. The sensitivity and specificity of ECV fraction were 78.43% and 71.43%, respectively. The combined parameter consisting of AP-NIC, VP-NIC, DP-NIC, and ECV fraction yielded an AUC of 0.823, with sensitivity of 76.47% and specificity of 77.14%. The sensitivity of the combined parameter was significantly higher than that of AP-NIC (P = 0.049). CONCLUSION It is valuable for dual-energy CT IC-based parameters and ECV fraction in preoperatively identifying type I and type II EOC. CRITICAL RELEVANCE STATEMENT Dual-energy CT-normalized iodine concentration and extracellular volume fraction achieved satisfactory discriminative efficacy, distinguishing between type I and type II epithelial ovarian carcinoma.
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Affiliation(s)
- Qingling Song
- Department of Radiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ye Li
- Department of Radiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Tingfan Wu
- United Imaging Research Institute of Innovative Medical Equipment, Shenzhen, China
| | - Wenjun Hu
- Department of Radiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yijun Liu
- Department of Radiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ailian Liu
- Department of Radiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
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Sutrisno S, Marlina D, Tjandraprawira KD, Adinda Adriansyah PN. The impact of pathogenic BRCA1/2 tumor mutation status on high grade serous epithelial ovarian cancer survival outcome: A multicenter study from Indonesia. SAGE Open Med 2024; 12:20503121241299849. [PMID: 39575313 PMCID: PMC11580090 DOI: 10.1177/20503121241299849] [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: 06/02/2024] [Accepted: 10/22/2024] [Indexed: 11/24/2024] Open
Abstract
Introduction Ovarian cancer is still a major health problem in Indonesia. development of breast cancer gene-related personalized medicine to increase the survival outcome of epithelial ovarian cancer patients in Indonesia is expected to be achieved. This research aims to evaluate the impact of pathogenic breast cancer gene 1 and breast cancer gene 2 tumor mutation on high-grade serous epithelial ovarian cancer survival outcome. Methods This study is an observational analytic study, using a historical cohort study design. A total of 68 from 144 patients diagnosed with International Federation of Gynecology and Obstetrics 2014 stage IIB-IV high-grade serous epithelial ovarian cancer between January 1st, 2015 until March 31st, 2021, at three centers in Jakarta. Next-generation sequencing tumor breast cancer gene 1 and breast cancer gene 2 testing and were included in this cohort historical study. We compared patient's overall survival outcomes, according to pathogenic breast cancer gene 1 and breast cancer gene 2 tumor mutational status. Clinicopathological characteristic factors that might affect patient's survival outcomes were also investigated. Results In the group of individuals with pathogenic breast cancer gene 1 and breast cancer gene 2 tumour mutations, the risk of death was significantly lower by 86% (adjusted RR 0.149; 95% CI: 0.046-0.475; p-value = 0.001), and the median survival time was significantly better (median 46 months; 95% CI: 34.009-57.991; p-value = 0.001) compared to the group without pathogenic breast cancer gene 1 and breast cancer gene 2 tumor mutations (median 23 months; 95% CI: 15.657-30.343; p-value = 0.001). The multivariate analysis revealed that the presence of a pathogenic breast cancer gene 1 and breast cancer gene 2 tumor mutation is an independent and positive prognostic factor for survival outcome. The adjusted relative risk was 0.149, with a 95% CI of 0.046-0.475, p-value = 0.001. Conclusions In high-grade serous ovarian cancer patients, the pathogenic breast cancer gene 1 and breast cancer gene 2 tumor mutations group have a better prognosis with longer survival outcomes than those without pathogenic breast cancer gene 1 and breast cancer gene 2 tumor mutations.
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Affiliation(s)
- Sutrisno Sutrisno
- Division of Gynecologic Oncology, Faculty of Medicine, Department of Obstetrics and Gynecology, Indonesia University, Dr. Cipto Mangunkusumo National Central Referral Hospital, Central Jakarta, Indonesia
| | - Dina Marlina
- Faculty of Medicine, Department of Obstetrics and Gynecology, Universitas Padjadjaran—Dr. Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Kevin Dominique Tjandraprawira
- Faculty of Medicine, Department of Obstetrics and Gynecology, Universitas Padjadjaran—Dr. Hasan Sadikin General Hospital, Bandung, Indonesia
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Lee YJ, Kim W, Hong S, Lee YJ, Lee JY, Kim SW, Kim S, Kim YT, Nam EJ. The effectiveness of CA125 and HE4 as clinical prognostic markers in epithelial ovarian cancer patients with BRCA mutation. J Gynecol Oncol 2024; 35:e80. [PMID: 38670560 PMCID: PMC11543245 DOI: 10.3802/jgo.2024.35.e80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 02/14/2024] [Accepted: 03/11/2024] [Indexed: 04/28/2024] Open
Abstract
OBJECTIVE To investigate the efficacy of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in predicting survival outcomes based on breast cancer gene (BRCA) mutational status in epithelial ovarian cancer. METHODS Medical records of 448 patients diagnosed with epithelial ovarian cancer at a single tertiary institution in Korea were retrospectively analyzed. Area under the curve, sensitivity, specificity, and accuracy were assessed using the CA125 and HE4 values after surgery and 3 cycles of chemotherapy to predict 1-year survival based on the BRCA mutational status. Kaplan-Meier analysis was used to obtain progression-free and overall survival to evaluate CA125 and HE4 effectiveness in predicting survival outcomes. RESULTS A total of 423 patients were analyzed, including 180 (42.6%) who underwent interval debulking surgery (IDS) and 243 (57.4%) who underwent primary debulking surgery (PDS). BRCA mutations were observed in 37 (15.2%) and 44 (22.4%) patients in the PDS and IDS groups, respectively. CA125 and HE4 normalization demonstrated the highest specificity in patients with or without BRCA mutations, with specificities of 97.1% and 99.1% in the PDS group and 78.6% and 86.2% in the IDS group, respectively. Normalizing HE4 alone may be an effective prognostic marker, with an area under the curve of 0.774 and specificity of 75.0%, in patients with BRCA mutations. CONCLUSION Normalizing both biomarkers emerged as the most effective predictive marker for the 1-year recurrence rate, regardless of BRCA mutational status. A negative HE4 value can be a useful predictor for 1-year recurrence-free survival in patients with BRCA mutations.
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Affiliation(s)
- Young Joo Lee
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Woojin Kim
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
- Korea Medical Institute, Seoul, Korea
| | - Soomin Hong
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Jae Lee
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jung-Yun Lee
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Wun Kim
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Sunghoon Kim
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Young Tae Kim
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Ji Nam
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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Chen L, Jin C, Chen B, Debora A, Su W, Zhou Q, Zhou S, Bian J, Yang Y, Lan L. A dual-center study: can ultrasound radiomics differentiate type I and type II epithelial ovarian cancer patients with normal CA125 levels? Br J Radiol 2024; 97:1706-1712. [PMID: 39177575 PMCID: PMC11417353 DOI: 10.1093/bjr/tqae144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 02/19/2024] [Accepted: 08/07/2024] [Indexed: 08/24/2024] Open
Abstract
OBJECTIVE CA125 is recommended by many countries as the primary screening test for ovarian cancer. But there are patients with ovarian cancer having normal CA125. We hope to identify the types of EOC with normal CA125 levels better by building a refined model based on the ultrasound radiomics, thus providing precise medical treatment for patients. METHODS We included 58 patients with EOC with normal CA125 from 2 centres, who were confirmed by preoperative ultrasound and pathology. We extracted 1130 radiomics features based on the tumour's region of interest from the most typical ultrasound image of each patient. We selected radiomics and clinical features by LASSO and logistic regression to construct Rad-score and clinical models, respectively. Receiver operating characteristic curves judged their test efficacy. On the basis of the combined model, we developed a nomogram. RESULTS Area under the curves (AUCs) of 0.93 and 0.83 were achieved in both the training and test groups for the combined model. There were similar AUCs between the Rad-score and clinical models of 0.82 and 0.80, respectively. By analysing the calibration curves, it was determined that the nomogram matched actual observations in the training cohort. CONCLUSION Ultrasound radiomics can differentiate type I and type II EOC with normal CA125 levels. ADVANCES IN KNOWLEDGE This study is the first to focus on EOC cases with normal level of CA125. The subset of patients constituting 20% of the disease population may require more refined radiomics models.
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Affiliation(s)
- Lixuan Chen
- The Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Chenyang Jin
- Department of Ultrasound, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Bo Chen
- The Department of Medical Record, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Asta Debora
- The Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Weizeng Su
- The Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Qingwen Zhou
- The Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Shuai Zhou
- The Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Jinyan Bian
- Department of Obstetrics and Gynecology Ultrasound, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Yunjun Yang
- The Department of Nuclear, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Li Lan
- The Department of Ultrasound, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
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Bhadra M, Sachan M, Nara S. Current strategies for early epithelial ovarian cancer detection using miRNA as a potential tool. Front Mol Biosci 2024; 11:1361601. [PMID: 38690293 PMCID: PMC11058280 DOI: 10.3389/fmolb.2024.1361601] [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: 12/26/2023] [Accepted: 03/20/2024] [Indexed: 05/02/2024] Open
Abstract
Ovarian cancer is one of the most aggressive and significant malignant tumor forms in the female reproductive system. It is the leading cause of death among gynecological cancers owing to its metastasis. Since its preliminary disease symptoms are lacking, it is imperative to develop early diagnostic biomarkers to aid in treatment optimization and personalization. In this vein, microRNAs, which are short sequence non-coding molecules, displayed great potential as highly specific and sensitive biomarker. miRNAs have been extensively advocated and proven to serve an instrumental part in the clinical management of cancer, especially ovarian cancer, by promoting the cancer cell progression, invasion, delayed apoptosis, epithelial-mesenchymal transition, metastasis of cancer cells, chemosensitivity and resistance and disease therapy. Here, we cover our present comprehension of the most up-to-date microRNA-based approaches to detect ovarian cancer, as well as current diagnostic and treatment strategies, the role of microRNAs as oncogenes or tumor suppressor genes, and their significance in ovarian cancer progression, prognosis, and therapy.
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Shi H, Liu L, Deng X, Xing X, Zhang Y, Djouda Rebecca Y, Han L. Exosomal biomarkers in the differential diagnosis of ovarian tumors: the emerging roles of CA125, HE4, and C5a. J Ovarian Res 2024; 17:4. [PMID: 38178252 PMCID: PMC10768525 DOI: 10.1186/s13048-023-01336-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 12/25/2023] [Indexed: 01/06/2024] Open
Abstract
OBJECTIVE Investigating the utility of serum exosomal markers CA125, HE4, and C5a, both individually and in combination, for distinguishing between benign and malignant ovarian tumors. METHODS In this study, we selected a total of 234 patients diagnosed with ovarian tumors, including 34 with malignant tumors, 10 with borderline ovarian tumors, and 190 with benign tumors. This study conducted comparisons of exosomal levels of CA125, HE4, and C5a among distinct groups, as well as making comparisons between serum and exosomal levels of CA125 and HE4. Furthermore, the diagnostic performance was assessed through Receiver Operating Characteristic (ROC) curve analysis. The Area Under the Curve (AUC) was computed, and a comparative evaluation of sensitivity and specificity was conducted to ascertain their effectiveness in determining the nature of ovarian tumors across different markers. RESULTS Serum CA125 and HE4 levels, the ROMA index, exosomal CA125, HE4, C5a levels, and their combined applied value (OCS value) were notably elevated in the ovarian non-benign tumor group compared to the benign tumor group, with statistical significance (P < 0.05). Exosomal and serum levels of CA125 and HE4 exhibited a positive correlation, with concentrations of these markers in serum surpassing those in exosomes. The combined OCS (AUC = 0.871) for CA125, HE4, and C5a in exosomes demonstrated superior sensitivity (0.773) and specificity (0.932) compared to serum tumor markers (CA125, HE4) and the ROMA index. The tumor stage represents an autonomous risk factor influencing the prognosis of individuals with ovarian malignancies. CONCLUSION The stage of ovarian malignancy is an independent risk factor for its prognosis. The combination of exosomal CA125, HE4 and C5a has a higher clinical value for the identification of the nature of ovarian tumours.
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Affiliation(s)
- Huihui Shi
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Liya Liu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Xueli Deng
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Xiaoyu Xing
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Yan Zhang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Yemeli Djouda Rebecca
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Liping Han
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China.
- , 1 East Jianshe Road, Zhengzhou, 450052, China.
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Hu C, Qin Z, Fu J, Gao Q, Chen C, Tan CS, Li S. Aptamer-based carbohydrate antigen 125 sensor with molybdenum disulfide functional hybrid materials. Anal Biochem 2023:115213. [PMID: 37355027 DOI: 10.1016/j.ab.2023.115213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/05/2023] [Accepted: 06/10/2023] [Indexed: 06/26/2023]
Abstract
Epithelial ovarian cancer is a malignant tumor of the female reproductive system with insidious symptoms, aggressiveness, risk of metastasis, and high mortality. Carbohydrate antigen 125 (CA125), a standard biomarker for screening epithelial ovarian cancer, can be applied to track cancer progression and treatment response. Here, we constructed an aptamer-based electrochemical biosensor to achieve sensitive detection of CA125. Molybdenum disulfide (MoS2) was used as the stable layered substrate, combined with the irregular branched structure of gold nanoflowers (AuNFs) to provide the sensing interface with a large specific surface area by one-step electrodeposition AuNFs@MoS2. The simplified electrode modification step increased the stability of the electrode while ensuring excellent electrochemical performance and providing many sulfhydryl binding sites. Then, AuNFs@MoS2/CA125 aptamer/MCH sensor was designed for CA125 detection. Based on AuNFs@MoS2 electrode, CA125 aptamer with sulfhydryl as the sensitive layer was fixed on the electrode by gold sulfur bonds. 6-Mercapto-1-hexanol (MCH) was used to block the electrode and reduce the non-specific adsorption. Finally, DPV analysis was applied for CA125 detection with the range of 0.0001 U/mL to 500 U/mL. Our designed aptamer sensor showed reasonable specificity, reproducibility, and stability. Clinical sample testing also proved the consistency of our sensor with the gold standard in negative/positive judgment. This work demonstrated a novel strategy for integrating nanostructures and biocompatibility to build advanced cancer biomarker sensors with promising applications.
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Affiliation(s)
- Chang Hu
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China; Tianjin International Engineering Institute, Tianjin University, Tianjin, 300072, China
| | - Ziyue Qin
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
| | - Jie Fu
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
| | - Qiya Gao
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China
| | - Chong Chen
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China; Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Cherie S Tan
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China.
| | - Shuang Li
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300072, China.
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Jiang YL, Fu XY, Yin ZH. Retrospective efficacy analysis of olaparib combined with bevacizumab in the treatment of advanced colorectal cancer. World J Gastrointest Surg 2023; 15:906-916. [PMID: 37342840 PMCID: PMC10277937 DOI: 10.4240/wjgs.v15.i5.906] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/11/2023] [Accepted: 04/07/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a highly prevalent malignancy of the digestive tract worldwide, characterized by a significant morbidity and mortality rate and subtle initial symptoms. Diarrhea, local abdominal pain, and hematochezia occur with the development of cancer, while systemic symptoms such as anemia and weight loss occur in patients with advanced CRC. Without timely interventions, the disease can have fatal consequences within a short span. The current therapeutic options for colon cancer include olaparib and bevacizumab, which are widely utilized. This study intends to evaluate the clinical efficacy of olaparib combined with bevacizumab in the treatment of advanced CRC, hoping to provide insights into advanced CRC treatment.
AIM To investigate the retrospective efficacy of olaparib combined with bevacizumab in the treatment of advanced CRC.
METHODS A retrospective analysis was conducted on a cohort of 82 patients with advanced colon cancer who were admitted to the First Affiliated Hospital of the University of South China between January 2018 and October 2019. Among them, 43 patients subjected to the classical FOLFOX chemotherapy regimen were selected as the control group, and 39 patients undergoing treatment with olaparib combined with bevacizumab were selected as the observation group. Subsequent to different treatment regimens, the short-term efficacy, time to progression (TTP), and incidence rate of adverse reactions between the two groups were compared. Changes in serum-related indicators [vascular endothelial growth factor (VEGF), matrix metalloprotein-9 (MMP-9), cyclooxygenase-2 (COX-2)] and tumor markers [human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125), carbohydrate antigen 199 (CA199)] levels before and after treatment were compared between the two groups at the same time.
RESULTS The objective response rate was discovered to be 82.05%, and the disease control rate was 97.44% in the observation group, which were significantly higher than the respective rates of 58.14% and 83.72% in the control group (P < 0.05). The median TTP was 24 mo (95%CI: 19.987-28.005) in the control group and 37 mo (95%CI: 30.854-43.870) in the observation group. The TTP in the observation group was significantly better than that in the control group, and the difference held statistical significance (log-rank test value = 5.009, P = 0.025). Before treatment, no substantial difference was detected in serum VEGF, MMP-9, and COX-2 levels and tumor markers HE4, CA125, and CA199 levels between the two groups (P > 0.05). Following treatment with different regimens, the above indicators in the two groups were remarkably promoted (P < 0.05), VEGF, MMP-9, and COX-2 in the observation group were lower than those in the control group (P < 0.05), and HE4, CA125, and CA199 levels were also lower than those in the control group (P < 0.05). Vis-à-vis the control group, the total incidence of gastrointestinal reactions, thrombosis, bone marrow suppression, liver and kidney function injury, and other adverse reactions in the observation group was notably lowered, with the difference considered statistically significant (P < 0.05).
CONCLUSION Olaparib combined with bevacizumab in the treatment of advanced CRC demonstrates a strong clinical effect of delaying disease progression and reducing the serum levels of VEGF, MMP-9, COX-2 and tumor markers HE4, CA125 and CA199. Moreover, given its fewer adverse reactions, it can be regarded as a safe and reliable treatment option.
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Affiliation(s)
- Yi-Ling Jiang
- Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Xue-Yuan Fu
- Department of Anorectal, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Zhi-Hui Yin
- Department of Anorectal, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
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Ning L, Lang J, Long B, Wu L. Diagnostic value of circN4BP2L2 in type I and type II epithelial ovarian cancer. BMC Cancer 2022; 22:1210. [PMID: 36434559 PMCID: PMC9694909 DOI: 10.1186/s12885-022-10138-w] [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: 04/11/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND CircN4BP2L2 was previously identified to be significantly decreased in epithelial ovarian cancer (EOC) and was associated with disease progression. The aim of this study was to evaluate the diagnostic value of plasma circN4BP2L2 using the unifying model of type I and type II EOC. METHODS A total of 540 plasma samples were obtained from 180 EOC patients, 180 benign ovarian cyst patients, and 180 healthy volunteers. CircN4BP2L2 was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) were assessed using enzyme-linked immunosorbent assay (ELISA). Receiver operating curve (ROC), the area under the curve (AUC), sensitivity and specificity were estimated. RESULTS Low level of circN4BP2L2 was associated with advanced tumor stage (p < 0.01) in type I EOC. Decreased circN4BP2L2 was associated with lymph node metastasis (LNM) (p = 0.04) in type II EOC. The expression level of circN4BP2L2 in type I was similar to that in type II. CircN4BP2L2 could significantly separate type I or type II from benign or normal cohort (p < 0.01). Early-stage type I or type II EOC vs. benign or normal cohort could also be distinguished by circN4BP2L2 (p < 0.01). CONCLUSION CircN4BP2L2 might serve as a promising diagnostic biomarker for both type I and type II EOC. The diagnostic safety for circN4BP2L2 in early-stage type I or type II EOC is also acceptable. Further large-scale well-designed studies are warranted to investigate whether circN4BP2L2 is specific for all histologic subgroups.
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Affiliation(s)
- Li Ning
- grid.506261.60000 0001 0706 7839Department of gynecologic oncology, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China
| | - Jinghe Lang
- grid.506261.60000 0001 0706 7839Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730 Beijing, China
| | - Bo Long
- grid.506261.60000 0001 0706 7839Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730 Beijing, China
| | - Lingying Wu
- grid.506261.60000 0001 0706 7839Department of gynecologic oncology, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China
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11
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Yao F, Ding J, Lin F, Xu X, Jiang Q, Zhang L, Fu Y, Yang Y, Lan L. Nomogram based on ultrasound radiomics score and clinical variables for predicting histologic subtypes of epithelial ovarian cancer. Br J Radiol 2022; 95:20211332. [PMID: 35612547 PMCID: PMC10162053 DOI: 10.1259/bjr.20211332] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 05/11/2022] [Accepted: 05/19/2022] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVE Ovarian cancer is one of the most common causes of death in gynecological tumors, and its most common type is epithelial ovarian cancer (EOC). This study aimed to establish a radiomics signature based on ultrasound images to predict the histopathological types of EOC. METHODS Overall, 265 patients with EOC who underwent preoperative ultrasonography and surgery were eligible. They were randomly sorted into two cohorts (training cohort: test cohort = 7:3). We outlined the region of interest of the tumor on the ultrasound images of the lesion. Then, the radiomics features were extracted. Clinical, Rad-score and combined models were constructed based on the least absolute shrinkage, selection operator, and logistic regression analysis. The performance of the models was evaluated using receiver operating characteristic curves and decision curve analysis (DCA). A nomogram was formulated based on the combined prediction model. RESULTS The combined model had good performance in predicting EOC histopathological types, with an AUC of 0.83 (95% CI: 0.77-0.90) and 0.82 (95% CI: 0.71-0.93) in the training and test cohorts, respectively. The calibration curves showed that the nomogram estimation was consistent with the actual observations. DCA also verified the clinical value of the combined model. CONCLUSIONS The combined model containing clinical and ultrasound radiomics features showed an excellent performance in predicting type I and type II EOC. ADVANCES IN KNOWLEDGE This study presents the first application of ultrasound radiomics features to distinguish EOC histopathological types. The proposed clinical-radiomics nomogram could help gynecologists non-invasively identify EOC types before surgery.
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Affiliation(s)
- Fei Yao
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jie Ding
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Feng Lin
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaomin Xu
- Department of Ultrasound imaging, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qi Jiang
- School of First Clinical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Li Zhang
- School of First Clinical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Yanqi Fu
- School of First Clinical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Yunjun Yang
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li Lan
- Department of Ultrasound imaging, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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12
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Manasa G, Mascarenhas RJ, Shetti NP, Malode SJ, Aminabhavi TM. Biomarkers for Early Diagnosis of Ovarian Carcinoma. ACS Biomater Sci Eng 2022; 8:2726-2746. [PMID: 35762531 DOI: 10.1021/acsbiomaterials.2c00390] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The leading cause of gynecological cancer-related morbidity and mortality is ovarian cancer (OC), which is dubbed a silent killer. Currently, OC is a target of intense biomarker research, because it is often not discovered until the disease is advanced. The goal of OC research is to develop effective tests using biomarkers that can detect the disease at the earliest stages, which would eventually decrease the mortality, thereby preventing recurrence. Therefore, there is a pressing need to revisit the existing biomarkers to recognize the potential biomarkers that can lead to efficient predictors for the OC diagnosis. This Perspective covers an update on the currently available biomarkers used in the triaging of OC to gain certain insights into the potential role of these biomarkers and their estimation that are crucial to the understanding of neoplasm progression, diagnostics, and therapy.
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Affiliation(s)
- G Manasa
- Electrochemistry Research Group, St. Joseph's College, Lalbagh Road, Bangalore - 560027, Karnataka, India
| | - Ronald J Mascarenhas
- Electrochemistry Research Group, St. Joseph's College, Lalbagh Road, Bangalore - 560027, Karnataka, India
| | - Nagaraj P Shetti
- Department of Chemistry, School of Advanced Sciences, KLE Technological University, Vidhyanagar, Hubballi - 580031, Karnataka, India
| | - Shweta J Malode
- Department of Chemistry, School of Advanced Sciences, KLE Technological University, Vidhyanagar, Hubballi - 580031, Karnataka, India
| | - Tejraj M Aminabhavi
- Department of Chemistry, School of Advanced Sciences, KLE Technological University, Vidhyanagar, Hubballi - 580031, Karnataka, India
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13
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Beirne JP, Gilmore A, McInerney CE, Roddy A, Glenn McCluggage W, Harley IJ, Abdullah Alvi M, Prise KM, McArt DG, Mullan PB. A bespoke target selection tool to guide biomarker discovery in tubo-ovarian cancer. Comput Struct Biotechnol J 2022; 20:3359-3371. [PMID: 35832628 PMCID: PMC9260242 DOI: 10.1016/j.csbj.2022.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 06/09/2022] [Accepted: 06/09/2022] [Indexed: 11/26/2022] Open
Abstract
Introduction Cancers presenting at advanced stages inherently have poor prognosis. High grade serous carcinoma (HGSC) is the most common and aggressive form of tubo-ovarian cancer. Clinical tests to accurately diagnose and monitor this condition are lacking. Hence, development of disease-specific tests are urgently required. Methods The molecular profile of HGSC during disease progression was investigated in a unique patient cohort. A bespoke data browser was developed to analyse gene expression and DNA methylation datasets for biomarker discovery. The Ovarian Cancer Data Browser (OCDB) is built in C# with a.NET framework using an integrated development environment of Microsoft Visual Studio and fast access files (.faf). The graphical user interface is easy to navigate between four analytical modes (gene expression; methylation; combined gene expression and methylation data; methylation clusters), with a rapid query response time. A user should first define a disease progression trend for prioritising results. Single or multiomics data are then mined to identify probes, genes and methylation clusters that exhibit the desired trend. A unique scoring system based on the percentage change in expression/methylation between disease stages is used. Results are filtered and ranked using weighting and penalties. Results The OCDB’s utility for biomarker discovery is demonstrated with the identified target OSR2. Trends in OSR2 repression and hypermethylation with HGSC disease progression were confirmed in the browser samples and an independent cohort using bioassays. The OSR2 methylation biomarker could discriminate HGSC with high specificity (95%) and sensitivity (93.18%). Conclusions The OCDB has been refined and validated to be an integral part of a unique biomarker discovery pipeline. It may also be used independently to aid identification of novel targets. It carries the potential to identify further biomarker assays that can reduce type I and II errors within clinical diagnostics.
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14
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Plasma circN4BP2L2 is a promising novel diagnostic biomarker for epithelial ovarian cancer. BMC Cancer 2022; 22:6. [PMID: 34980005 PMCID: PMC8721970 DOI: 10.1186/s12885-021-09073-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/17/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) are more stable than linear RNA molecules, which makes them promising diagnostic biomarkers for diseases. By circRNA-sequencing analysis, we previously found that circN4BP2L2 was significantly decreased in epithelial ovarian cancer (EOC) tissues, and was predictive of disease progression. The aim of this study was to evaluate the diagnostic value of plasma circN4BP2L2 in EOC. METHODS Three hundred seventy-eight plasma samples were acquired prior to surgery. Samples were obtained from 126 EOC patients, 126 benign ovarian cyst patients, and 126 healthy volunteers. CircN4BP2L2 was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) were assessed using enzyme-linked immunosorbent assay (ELISA). EOC cells were transfected with small interference RNAs (siRNAs) and cell proliferation, migration, invasion, cell cycle and cell apoptosis were performed to assess the effect of circN4BP2L2 in EOC. Receiver operating curve (ROC), the area under the curve (AUC), sensitivity and specificity were estimated. RESULTS Plasma circN4BP2L2 was significantly downregulated in EOC patients. Decreased circN4BP2L2 was significantly associated with advanced tumor stage, worse histological grade, lymph node metastasis and distant metastasis in EOC. CircN4BP2L2 inhibited tumor cell migration and invasion in vitro. CircN4BP2L2 could significantly separate EOC from benign (AUC = 0.82, P < 0.01) or normal (AUC = 0.90, P < 0.01) cohort. Early stage EOC vs benign (AUC = 0.81, P < 0.01) or normal (AUC = 0.90, P < 0.01) cohort could also be distinguished by circN4BP2L2. In discrimination between EOC cohort and benign or normal cohort, circN4BP2L2 performed equally well in both pre- and post-menopausal women. The combination of circN4BP2L2, CA125 and HE4 showed high sensitivity and specificity in detecting EOC cases. CONCLUSIONS Plasma circN4BP2L2 is significantly downregulated in EOC and might serve as a promising novel diagnostic biomarker for EOC patients, especially in early stage EOC cases. CircN4BP2L2 might act as an adjunct to CA125 and HE4 in detecting EOC. Further large-scale studies are warranted to verify our results.
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15
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Blackman A, Mitchell J, Rowswell-Turner R, Singh R, Kim KK, Eklund E, Skates S, Bast RC, Messerlian G, Miller MC, Moore RG. Analysis of serum HE4 levels in various histologic subtypes of epithelial ovarian cancer and other malignant tumors. Tumour Biol 2021; 43:355-365. [DOI: 10.3233/tub-211546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported. OBJECTIVE: The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies. METHODS: Data from six prospective pelvic mass clinical trials was combined and an evaluation of serum HE4 levels in women diagnosed with a malignancy was performed. For all patients, serum was obtained prior to surgery and final pathology, including primary tumor site, histologic subtype, grade and stage, were recorded. The mean, median, standard deviation, maximum, and minimum HE4 levels were determined for each group. RESULTS: A total of 984 patients were included in this study, with the average patient age being 60 years old. There were 230 premenopausal and 754 postmenopausal patients. Serum HE4 levels were elevated (≥70.0 pMol) in 85%of EOCs, 40%of LMP tumors, 21%of non-EOCs (germ cell tumors), 25%of cervical cancers, and 47%of non-gynecologic metastatic cancers. Analysis of histologic subtypes revealed 90%(n = 391) of serous, 85%(n = 73) of endometrioid, 45%(n = 42) of mucinous, 86%(n = 51) of mixed tumors, and 69%(n = 36) of clear cell tumors had elevated serum HE4 levels. CONCLUSIONS: Serum HE4 levels are most often elevated in women with high grade serous and endometrioid EOCs, and though serum elevations are seen more often with advanced stage disease, HE4 is also often elevated in early stage disease and lower grade tumors.
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Affiliation(s)
- Alexandra Blackman
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Jessica Mitchell
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Rachael Rowswell-Turner
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Rakesh Singh
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Kyu Kwang Kim
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Elizabeth Eklund
- Department of Pathology, Women and Infants Hospital, Brown University, RI, USA
| | - Steven Skates
- Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | - Robert C. Bast
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Geralyn Messerlian
- Department of Pathology, Women and Infants Hospital, Brown University, RI, USA
| | - M. Craig Miller
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
| | - Richard G. Moore
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
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Soibi-Harry AP, Amaeshi LC, Garba SR, Anorlu RI. The relationship between pre-operative lymphocyte to monocyte ratio and serum cancer antigen-125 among women with epithelial ovarian cancer in Lagos, Nigeria. Ecancermedicalscience 2021; 15:1288. [PMID: 34824611 PMCID: PMC8580589 DOI: 10.3332/ecancer.2021.1288] [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: 02/27/2021] [Indexed: 12/09/2022] Open
Abstract
Ovarian cancer (OC) is the second most common genital cancer worldwide, and the most lethal of all genital cancers. The role of inflammation and markers of systemic inflammation such as neutrophils, lymphocytes and monocytes in cancer biology have been investigated and reported in many studies. Cancer antigen 125 (CA-125) is currently in use as an adjunct to diagnosis, prognostication and monitoring of epithelial OC (EOC). This test is not readily available in many centres in sub-Saharan Africa, creating a need to identify alternative markers that are available and affordable. This study aimed to determine the relationship between pre-operative serum lymphocyte to monocyte ratio (LMR) and CA-125 in EOC. This was a retrospective cross-sectional study among 70 women, diagnosed with EOC in Lagos University Teaching Hospital from January 2013 to December 2019. Data were extracted from the case notes of the patients. LMR was calculated as the absolute lymphocyte count divided by the absolute monocyte count and analysed using Statistical Package for Social Sciences (SPSS) version 25.0. The correlation between LMR and CA-125 was determined using Pearson’s correlation coefficient. The mean age of the patients was 48.57 ± 13.97 years. Serous adenocarcinoma was the most common subtype of EOC making up 94.3% of the cases. The median serum CA-125 was 393.5 (215.00–765.67) U/mL. The median LMR was 6.77 (1.28–43.0). There was a statistically significant negative correlation between CA-125 and LMR, r = −0.28, p = 0.02. LMR was negatively associated with CA-125 in women with EOC. LMR may be considered as a simple, affordable alternative marker to CA-125 in the management of EOC.
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Affiliation(s)
- Adaiah Priscilla Soibi-Harry
- Oncology & Pathological Studies Unit, Department of Obstetrics & Gynaecology, Lagos University Teaching Hospital, Lagos 101233, Nigeria
| | - Lemchukwu Chukwunonye Amaeshi
- Clinical Haematology and Oncology Unit, Department of Medicine, Lagos University Teaching Hospital, Lagos 101233, Nigeria
| | - Sunusi Rimi Garba
- Oncology & Pathological Studies Unit, Department of Obstetrics & Gynaecology, Lagos University Teaching Hospital, Lagos 101233, Nigeria
| | - Rose Ihuoma Anorlu
- Department of Obstetrics & Gynaecology, University of Lagos/Lagos University Teaching Hospital, Lagos 101233, Nigeria
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Vinod R, Mahran R, Routila E, Leivo J, Pettersson K, Gidwani K. Nanoparticle-Aided Detection of Colorectal Cancer-Associated Glycoconjugates of Extracellular Vesicles in Human Serum. Int J Mol Sci 2021; 22:ijms221910329. [PMID: 34638669 PMCID: PMC8508761 DOI: 10.3390/ijms221910329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/18/2021] [Accepted: 09/20/2021] [Indexed: 11/16/2022] Open
Abstract
Extracellular vesicles (EVs) are found in all biological fluids, providing potential for the identification of disease biomarkers such as colorectal cancer (CRC). EVs are heavily glycosylated with specific glycoconjugates such as tetraspanins, integrins, and mucins, reflecting the characteristics of the original cell offering valuable targets for detection of CRC. We report here on europium-nanoparticle (EuNP)-based assay to detect and characterize different surface glycoconjugates of EVs without extensive purification steps from five different CRC and the HEK 293 cell lines. The promising EVs candidates from cell culture were clinically evaluated on small panel of serum samples including early-stage (n = 11) and late-stage (n = 11) CRC patients, benign condition (n = 11), and healthy control (n = 10). The majority of CRC cell lines expressed tetraspanin sub-population and glycovariants of integrins and conventional tumor markers. The subpopulation of CD151 having CD63 expression (CD151CD63) was significantly (p = 0.001) elevated in early-stage CRC (8 out of 11) without detecting any benign and late-stage samples, while conventional CEA detected mostly late-stage CRC (p = 0.045) and with only four early-stage cases. The other glycovariant assays such as CEACon-A, CA125WGA, CA 19.9Ma696, and CA 19.9Con-A further provided some complementation to the CD151CD63 assay. These results indicate the potential application of CD151CD63 assay for early detection of CRC patients in human serum.
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Affiliation(s)
- Rufus Vinod
- Department of Life Technologies, University of Turku, 20520 Turku, Finland; (R.V.); (R.M.); (E.R.); (J.L.); (K.P.)
| | - Randa Mahran
- Department of Life Technologies, University of Turku, 20520 Turku, Finland; (R.V.); (R.M.); (E.R.); (J.L.); (K.P.)
- Tropical Health and Parasitology Department, High Institute of Public Health, Alexandria University, Alexandria 21617, Egypt
| | - Erica Routila
- Department of Life Technologies, University of Turku, 20520 Turku, Finland; (R.V.); (R.M.); (E.R.); (J.L.); (K.P.)
| | - Janne Leivo
- Department of Life Technologies, University of Turku, 20520 Turku, Finland; (R.V.); (R.M.); (E.R.); (J.L.); (K.P.)
| | - Kim Pettersson
- Department of Life Technologies, University of Turku, 20520 Turku, Finland; (R.V.); (R.M.); (E.R.); (J.L.); (K.P.)
| | - Kamlesh Gidwani
- Department of Life Technologies, University of Turku, 20520 Turku, Finland; (R.V.); (R.M.); (E.R.); (J.L.); (K.P.)
- Correspondence:
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Guo L, Song B, Xiao J, Lin H, Chen J, Su X. The Prognostic Value of Biomarkers on Detecting Non-Small Cell Lung Cancer in a Chinese Elderly Population. Int J Gen Med 2021; 14:5279-5286. [PMID: 34522127 PMCID: PMC8434877 DOI: 10.2147/ijgm.s331311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 08/23/2021] [Indexed: 12/25/2022] Open
Abstract
Background Survival in non-small cell lung cancer (NSCLC) remains poor. Early detection of NSCLC is of great significance to provide a chance to improve survival. Aim We constructed predictive models to evaluate the predictive value of four tumor biomarkers by including serum human epididymis protein 4 (HE4), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCA), and cytokeratin 19 fragment (CY21-1) on detecting NSCLC in a Chinese elderly population. Methods A total of 363 patients with NSCLC and 433 subjects without cancer (healthy control group) were admitted to the respiratory department in our hospital. We assessed serum levels of these four tumor biomarkers in the two groups and then the predictive value of predictive models was evaluated. Results Serum median values of HE4 (143.3 pmol/L), CEA (4.60 ng/mL), SCCA (1.52 ng/mL), and CY21-1 (5.36 ng/mL) in patients with NSCLC were significantly higher than the healthy control group, respectively (all P<0.05). A multivariate logistic regression model showed that HE4 (OR=2.10, 95% CI=1.22–4.42, P=0.013), CEA (OR=2.30, 95% CI=1.44–4.53, P=0.004), SCCA (OR=2.20, 95% CI=1.29–4.55, P=0.011), and CY21-1 (OR=2.60, 95% CI=1.56–6.25, P<0.001) were significantly and independently associated with increased risk of NSCLC on admission after confounding factors were corrected. Importantly, the ROC curve suggested HE4 had a good value on predicting NSCLC in the Chinese elderly population. Additionally, the predictive model (CEA+SCCA+CY21-1+HE4) had better idea capability to detecting the existence of NSCLC (AUC=0.954, 95% CI=0.927–0.999, P<0.001). Conclusion Our study showed that several lung cancer-related biomarkers were used to build prediction models, which has good value for early prediction of NSCLC.
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Affiliation(s)
- Lianghua Guo
- Department of Respiratory Medicine, Mindong Hospital of Fujian Medical University, Fuan City, 355000, People's Republic of China
| | - Bin Song
- Department of Respiratory Medicine, Mindong Hospital of Fujian Medical University, Fuan City, 355000, People's Republic of China
| | - Jianhong Xiao
- Department of Respiratory Medicine, Mindong Hospital of Fujian Medical University, Fuan City, 355000, People's Republic of China
| | - Hui Lin
- Department of Respiratory Medicine, Mindong Hospital of Fujian Medical University, Fuan City, 355000, People's Republic of China
| | - Junhua Chen
- Department of Respiratory Medicine, Mindong Hospital of Fujian Medical University, Fuan City, 355000, People's Republic of China
| | - Xianghua Su
- Department of Neurosurgery, Mindong Hospital of Fujian Medical University, Fuan City, 355000, People's Republic of China
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Lycke M, Ulfenborg B, Malchau Lauesgaard J, Kristjansdottir B, Sundfeldt K. Consideration should be given to smoking, endometriosis, renal function (eGFR) and age when interpreting CA125 and HE4 in ovarian tumor diagnostics. Clin Chem Lab Med 2021; 59:1954-1962. [PMID: 34388324 DOI: 10.1515/cclm-2021-0510] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/03/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES To evaluate the impact of different biologic, histopathologic and lifestyle factors on serum levels of human epididymis protein 4 (HE4) and Cancer antigen 125 (CA125) in the diagnostic work up of women with an ovarian cyst or pelvic tumor. METHODS The statistical evaluation was performed on a population of 445 women diagnosed with a benign ovarian disease, included in a large Swedish multicenter trial (ClinicalTrials.gov NCT03193671). Multivariable logistic regression analyses were performed to distinguish between the true negatives and false positives through adjusting for biologic, histopathologic and lifestyle factors on serum samples of CA125 and HE4 separately. The likelihood ratio test was used to determine statistical significance and Benjamini-Hochberg correction to adjust for multiple testing. RESULTS A total of 31% of the women had false positive CA125 but only 9% had false positive results of HE4. Smoking (OR 6.62 95% CI 2.93-15.12) and impaired renal function, measured by eGFR (OR 0.18 95% CI 0.08-0.39), were independently predictive of falsely elevated serum levels of HE4. Endometriosis was the only variable predictive of falsely elevated serum levels of CA125 (OR 7.96 95% CI 4.53-14.39). Age correlated with increased serum levels of HE4. CONCLUSIONS Smoking, renal failure, age and endometriosis are factors that independently should be considered when assessing serum levels of HE4 and CA125 in women with an ovarian cyst or pelvic mass to avoid false indications of malignant disease.
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Affiliation(s)
- Maria Lycke
- Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg and Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - Jacob Malchau Lauesgaard
- Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg and Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Björg Kristjansdottir
- Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg and Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Karin Sundfeldt
- Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg and Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
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CA125 and Ovarian Cancer: A Comprehensive Review. Cancers (Basel) 2020; 12:cancers12123730. [PMID: 33322519 PMCID: PMC7763876 DOI: 10.3390/cancers12123730] [Citation(s) in RCA: 218] [Impact Index Per Article: 43.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/27/2022] Open
Abstract
Simple Summary CA125 has been the most promising biomarker for screening ovarian cancer; however, it still does not have an acceptable accuracy in population-based screening for ovarian cancer. In this review article, we have discussed the role of CA125 in diagnosis, evaluating response to treatment and prognosis of ovarian cancer and provided some suggestions in improving the clinical utility of this biomarker in the early diagnosis of aggressive ovarian cancers. These include using CA125 to screen individuals with symptoms who seek medical care rather than screening the general population, increasing the cutoff point for the CA125 level in the plasma and performing the test at point-of-care rather than laboratory testing. By these strategies, we would detect more aggressive ovarian cancer patients in stages that the tumour can be completely removed by surgery, which is the most important factor in redusing recurrence rate and improving the survival of the patients with ovarian cancer. Abstract Ovarian cancer is the second most lethal gynecological malignancy. The tumour biomarker CA125 has been used as the primary ovarian cancer marker for the past four decades. The focus on diagnosing ovarian cancer in stages I and II using CA125 as a diagnostic biomarker has not improved patients’ survival. Therefore, screening average-risk asymptomatic women with CA125 is not recommended by any professional society. The dualistic model of ovarian cancer carcinogenesis suggests that type II tumours are responsible for the majority of ovarian cancer mortality. However, type II tumours are rarely diagnosed in stages I and II. The recent shift of focus to the diagnosis of low volume type II ovarian cancer in its early stages of evolution provides a new and valuable target for screening. Type II ovarian cancers are usually diagnosed in advanced stages and have significantly higher CA125 levels than type I tumours. The detection of low volume type II carcinomas in stage IIIa/b is associated with a higher likelihood for optimal cytoreduction, the most robust prognostic indicator for ovarian cancer patients. The diagnosis of type II ovarian cancer in the early substages of stage III with CA125 may be possible using a higher cutoff point rather than the traditionally used 35 U/mL through the use of point-of-care CA125 assays in primary care facilities. Rapid point-of-care testing also has the potential for effective longitudinal screening and quick monitoring of ovarian cancer patients during and after treatment. This review covers the role of CA125 in the diagnosis and management of ovarian cancer and explores novel and more effective screening strategies with CA125.
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Feeney L, Harley IJG, McCluggage WG, Mullan PB, Beirne JP. Liquid biopsy in ovarian cancer: Catching the silent killer before it strikes. World J Clin Oncol 2020; 11:868-889. [PMID: 33312883 PMCID: PMC7701910 DOI: 10.5306/wjco.v11.i11.868] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 07/29/2020] [Accepted: 11/04/2020] [Indexed: 02/06/2023] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy in the western world. The majority of women presenting with the disease are asymptomatic and it has been dubbed the "silent killer". To date there is no effective minimally invasive method of stratifying those with the disease or screening for the disease in the general population. Recent molecular and pathological discoveries, along with the advancement of scientific technology, means there is a real possibility of having disease-specific liquid biopsies available within the clinical environment in the near future. In this review we discuss these discoveries, particularly in relation to the most common and aggressive form of EOC, and their role in making this possibility a reality.
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Affiliation(s)
- Laura Feeney
- Patrick G Johnston Centre for Cancer Research, Queens University, Belfast BT9 7AE, United Kingdom
| | - Ian JG Harley
- Northern Ireland Gynaecological Cancer Centre, Belfast Health and Social Care Trust, Belfast BT9 7AB, United Kingdom
| | - W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Belfast BT12 6BL, United Kingdom
| | - Paul B Mullan
- Patrick G Johnston Centre for Cancer Research, Queens University, Belfast BT9 7AE, United Kingdom
| | - James P Beirne
- Trinity St James Cancer Institute, St. James’ Hospital, Dublin 8, Ireland
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22
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Kanduc D. Oligopeptides for Immunotherapy Approaches in Ovarian Cancer Treatment. Curr Drug Discov Technol 2020; 16:285-289. [PMID: 29793409 DOI: 10.2174/1570163815666180525071740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 05/11/2018] [Accepted: 05/21/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Anti-ovarian cancer vaccines based on minimal immune determinants uniquely expressed in ovarian cancer biomarkers appear to promise a high level of sensitivity and specificity for ovarian cancer immunodiagnostics, immunoprevention, and immunotherapy. METHODS Using the Pir Peptide Match program, three ovarian cancer biomarkers - namely, sperm surface protein Sp17, WAP four-disulfide core domain protein 2, and müllerian-inhibiting substance - were searched for unique peptide segments not shared with other human proteins. Then, the unique peptide segments were assembled to define oligopeptides potentially usable as synthetic ovarian cancer antigens. RESULTS AND CONCLUSION This study describes a methodology for constructing ovarian cancer biomarkerderived oligopeptide constructs that might induce powerful, specific, and non-crossreactive immune responses against ovarian cancer.
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Affiliation(s)
- Darja Kanduc
- Department of Biosciences, Biotechnologies & Biopharmaceutics, University of Bari, Bari, Italy
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23
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Ferraro S, Panteghini M. Making new biomarkers a reality: the case of serum human epididymis protein 4. Clin Chem Lab Med 2020; 57:1284-1294. [PMID: 30511925 DOI: 10.1515/cclm-2018-1111] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 10/31/2018] [Indexed: 01/01/2023]
Abstract
Background Measurement of human epididymis protein 4 (HE4) in serum has recently been proposed for clinical use in the framework of ovarian cancer (OvCa). We sought to retrace the translational phase and the clinical implementation steps boosting HE4's clinical value and discuss the effects of its introduction on the diagnostic and management pathways. Methods Meta-analyses of running evidence have preliminarily suggested that HE4 may overcome carbohydrate antigen 125 (CA125) in identifying OvCa, showing however several gaps that need to be considered, i.e. definition of biomarker diagnostic performance in the early detection of OvCa, added diagnostic value, biological and lifestyle factors of variation, and optimal interpretative criteria. Investigation of the influencing factors has shown that renal impairment represents a major limitation for HE4's diagnostic power. On the other hand, the demonstration of the substantial equivalence of results obtained by commercially available assays allows recommending harmonized thresholds for diagnostic purpose, even if the study of HE4's biological variation has clarified that the longitudinal interpretation of the biomarker changes according to the reference change value could be more appropriate. Summary We used HE4 as an example for describing the long and bumpy road for making a new biomarker a reality, and the issues that should be checked and the information that should be provided in moving a novel biomarker from its discovery to an effective clinical adoption.
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Affiliation(s)
- Simona Ferraro
- UOC Patologia Clinica, Ospedale "Luigi Sacco", Via GB Grassi 74, 20157 Milano, Italy.,Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
| | - Mauro Panteghini
- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
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Increased Diagnostic Accuracy of Adnexal Tumors with A Combination of Established Algorithms and Biomarkers. J Clin Med 2020; 9:jcm9020299. [PMID: 31973047 PMCID: PMC7073859 DOI: 10.3390/jcm9020299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 01/10/2020] [Accepted: 01/18/2020] [Indexed: 12/26/2022] Open
Abstract
Ovarian cancer is the most lethal gynecologic cancer. Pre-diagnostic testing lacks sensitivity and specificity, and surgery is often the only way to secure the diagnosis. Exploring new biomarkers is of great importance, but the rationale of combining validated well-established biomarkers and algorithms could be a more effective way forward. We hypothesized that we can improve differential diagnostics and reduce false positives by combining (a) risk of malignancy index (RMI) with serum HE4, (b) risk of ovarian malignancy algorithm (ROMA) with a transvaginal ultrasound score or (c) adding HE4 to CA125 in a simple algorithm. With logistic regression modeling, new algorithms were explored and validated using leave-one-out cross validation. The analyses were performed in an existing cohort prospectively collected prior to surgery, 2013-2016. A total of 445 benign tumors and 135 ovarian cancers were included. All presented models improved specificity at cut-off compared to the original algorithm, and goodness of fit was significant (p < 0.001). Our findings confirm that HE4 is a marker that improves specificity without hampering sensitivity or diagnostic accuracy in adnexal tumors. We provide in this study "easy-to-use" algorithms that could aid in the triage of women to the most appropriate level of care when presenting with an unknown ovarian cyst or suspicious ovarian cancer.
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25
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Meng L, Nawaz MAH, Huang X, Ma Y, Li Y, Zhou H, Yu C. The use of aggregation-induced emission probe doped silica nanoparticles for the immunoassay of human epididymis protein 4. Analyst 2019; 144:6136-6142. [PMID: 31536063 DOI: 10.1039/c9an01265f] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
A sensitive sandwich immunoassay for the sensing of human epididymis protein 4 (HE4) is developed based on aggregation-induced emission probe doped silica nanoparticles. Fluorescent silica nanoparticles (TSiO2) with excellent performance were prepared using a tetraphenylethylene based probe (TPE-C4-4) to produce a controlled aggregation effect, and HE4 was detected using antibody-functionalized fluorescent silica nanoparticles. The fluorescent silica nanoparticles possess good photophysical properties. The TSiO2 NPs were surface modified with carboxyl groups, and the antibody was covalently attached onto the surface of the nanoparticles. In addition, magnetic beads were modified with N-hydroxysulfosuccinimide sodium salt (NHS) on their surface, capable of forming stable peptide bonds with the antibody. TSiO2 NPs modified by an antibody and the magnetic beads modified by an antibody were used for the sandwich immunoassay for HE4 protein. The assay is quite sensitive and selective. The detection limit of HE4 is estimated to be 40 pM. The assay shows promising applications for the early diagnosis of ovarian cancer and the development of ovarian cancer-related drugs.
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Affiliation(s)
- Lianjie Meng
- School of Changchun University of Science and Technology, Changchun, 130022, P. R. China.
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26
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Ahmed AA, Abdou AM. Diagnostic accuracy of CA125 and HE4 in ovarian carcinoma patients and the effect of confounders on their serum levels. Curr Probl Cancer 2019; 43:450-460. [DOI: 10.1016/j.currproblcancer.2018.12.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 11/19/2018] [Accepted: 12/21/2018] [Indexed: 12/18/2022]
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Ma X, Lakshmipriya T, Gopinath SCB. Recent Advances in Identifying Biomarkers and High-Affinity Aptamers for Gynecologic Cancers Diagnosis and Therapy. JOURNAL OF ANALYTICAL METHODS IN CHEMISTRY 2019; 2019:5426974. [PMID: 31583159 PMCID: PMC6754908 DOI: 10.1155/2019/5426974] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 08/04/2019] [Accepted: 08/21/2019] [Indexed: 05/28/2023]
Abstract
Cancer is the uncontrollable abnormal division of cell growth, caused due to the varied reasons. Cancer can be expressed in any part of the body, and it is one of the death-causing diseases. Human reproductive organs are commonly damaged by cancer. In particular, the women reproductive system is affected by various cancers including ovarian, cervical, endometrial, vaginal, fallopian tube, and vulvar cancers. Identifying these cancers at earlier stages prevents the damage to the organs. Aptamer is the potential probe that can identify these cancers. Aptamer is an artificial antibody selected from the randomized library of molecules and has a high binding affinity to the target biomarker. Targeting cancers in the reproductive organs using aptamers showed an excellent efficiency of detection compared to other probes. Different aptamers have been generated against the gynaecological cancer biomarkers, which include HE4, CA125, VEGF, OCCA (for ovarian cancer), EGFR, FGFR1, K-ras (for endometrial cancer), HPV E-16, HPV E-7, HPV E-6, tyrosine, and kinase (for cervical cancer), which help to identify the cancers in woman reproductive organs. In this overview, the biomarkers for gynecologic cancers and the relevant diagnosing systems generated using the specific aptamers are discussed. Furthermore, the therapeutic applications of aptamer with gynaecological cancers are narrated.
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Affiliation(s)
- Xiaoqun Ma
- Deparment of Gynecology, Taian City Central Hospital, Taian, Shandong 271000, China
| | - Thangavel Lakshmipriya
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, 01000 Kangar, Perlis, Malaysia
| | - Subash C. B. Gopinath
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, 01000 Kangar, Perlis, Malaysia
- School of Bioprocess Engineering, Universiti Malaysia Perlis, 02600 Arau, Perlis, Malaysia
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Discovery and Validation of Novel Biomarkers for Detection of Epithelial Ovarian Cancer. Cells 2019; 8:cells8070713. [PMID: 31336942 PMCID: PMC6678810 DOI: 10.3390/cells8070713] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/05/2019] [Accepted: 07/10/2019] [Indexed: 12/13/2022] Open
Abstract
Detection of epithelial ovarian cancer (EOC) poses a critical medical challenge. However, novel biomarkers for diagnosis remain to be discovered. Therefore, innovative approaches are of the utmost importance for patient outcome. Here, we present a concept for blood-based biomarker discovery, investigating both epithelial and specifically stromal compartments, which have been neglected in search for novel candidates. We queried gene expression profiles of EOC including microdissected epithelium and adjacent stroma from benign and malignant tumours. Genes significantly differentially expressed within either the epithelial or the stromal compartments were retrieved. The expression of genes whose products are secreted yet absent in the blood of healthy donors were validated in tissue and blood from patients with pelvic mass by NanoString analysis. Results were confirmed by the comprehensive gene expression database, CSIOVDB (Ovarian cancer database of Cancer Science Institute Singapore). The top 25% of candidate genes were explored for their biomarker potential, and twelve were able to discriminate between benign and malignant tumours on transcript levels (p < 0.05). Among them T-cell differentiation protein myelin and lymphocyte (MAL), aurora kinase A (AURKA), stroma-derived candidates versican (VCAN), and syndecan-3 (SDC), which performed significantly better than the recently reported biomarker fibroblast growth factor 18 (FGF18) to discern malignant from benign conditions. Furthermore, elevated MAL and AURKA expression levels correlated significantly with a poor prognosis. We identified promising novel candidates and found the stroma of EOC to be a suitable compartment for biomarker discovery.
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Enroth S, Berggrund M, Lycke M, Broberg J, Lundberg M, Assarsson E, Olovsson M, Stålberg K, Sundfeldt K, Gyllensten U. High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer. Commun Biol 2019; 2:221. [PMID: 31240259 PMCID: PMC6586828 DOI: 10.1038/s42003-019-0464-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 05/07/2019] [Indexed: 11/13/2022] Open
Abstract
Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations. The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85 and specificity = 0.93 for detection of ovarian cancer stages I-IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.
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Affiliation(s)
- Stefan Enroth
- Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Box 815, Uppsala University, SE-75108 Uppsala, Sweden
| | - Malin Berggrund
- Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Box 815, Uppsala University, SE-75108 Uppsala, Sweden
| | - Maria Lycke
- Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden
| | - John Broberg
- OLINK Proteomics, Uppsala Science Park, SE-751 83 Uppsala, Sweden
| | - Martin Lundberg
- OLINK Proteomics, Uppsala Science Park, SE-751 83 Uppsala, Sweden
| | - Erika Assarsson
- OLINK Proteomics, Uppsala Science Park, SE-751 83 Uppsala, Sweden
| | - Matts Olovsson
- Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
| | - Karin Stålberg
- Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
| | - Karin Sundfeldt
- Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden
| | - Ulf Gyllensten
- Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Box 815, Uppsala University, SE-75108 Uppsala, Sweden
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Significance of Serum Human Epididymis Protein 4 and Cancer Antigen 125 in Distinguishing Type I and Type II Epithelial Ovarian Cancers. Int J Gynecol Cancer 2019; 28:1058-1065. [PMID: 29975290 DOI: 10.1097/igc.0000000000001277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The objective of this study was to assess the effectiveness of human epididymis protein 4 (HE4) and cancer antigen 125 (CA125), and risk of ovarian malignancy algorithm (ROMA) in identifying type I and type II epithelial ovarian cancers (EOCs). METHODS A cross-sectional diagnostic study was conducted of 499 Thai women older than 18 years who had clinically diagnosed pelvic masses and underwent elective surgery at our hospital between July 2012 and July 2014. Preoperative serum HE4 and CA125 levels were measured, and postoperative pathologic slides were reviewed. RESULTS Of 499 Thai women enrolled in this study, 357 were noncancerous (NC), 79 had type I EOCs (EOCs-I) and 63 had type II (EOCs-II). Risk of ovarian malignancy algorithm revealed significantly better performance than HE4 and CA125 in discriminating between NC and EOCs-I (receiver operating characteristic curve and area under the curve [ROC-AUC]: ROMA, 0.86; HE4, 0.80; and CA125, 0.77), and NC and EOCs-II (ROC-AUC: ROMA, 0.97; HE4, 0.95; and CA125, 0.93). In differentiation between EOCs-I and EOCs-II (setting EOC-II as reference), ROMA yielded a better performance than HE4 and CA125 (ROC-AUC: ROMA, 0.83; HE4, 0.82; and CA125, 0.77); however, CA125 and HE4 showed higher sensitivity (CA125, 77.8%; HE4, 76.2%), whereas ROMA had the highest specificity (79.8%). CONCLUSIONS In women who present with pelvic masses, ROMA performed very well in distinguishing between noncancer lesions and EOCs but the combined HE4 and CA125 test was more effective in predicting EOC types.
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31
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Ovarian carcinomas express HE4 epitopes independently of each other. Cancer Treat Res Commun 2019; 21:100152. [PMID: 31226514 DOI: 10.1016/j.ctarc.2019.100152] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 05/16/2019] [Accepted: 05/23/2019] [Indexed: 11/23/2022]
Abstract
BACKGROUND The gene encoding HE4 undergoes alternative splicing to yield multiple protein isoforms. We investigated anti-HE4 mAbs which recognize epitopes on the C (2H5 and 3D8) or N (12A2 and 14E2) terminals. METHODS A Luminex assay was applied to determine mAb affinity. Binding of mAbs to sections from formaline fixed ovarian carcinomas was determined by immunohistology, binding to cultured ovarian carcinoma cells was tested by flow cytometry and immunocytochemistry, and HE4 secretion to patient serum or supernatants of cultured ovarian carcinoma was assayed by ELISA. RESULTS mAb 12A2 bound to formalin-fixed sections from 18 of 19 ovarian carcinomas, while 14E2, 2H5 and 3D8 bound to sections from 14, 7 and 4 patients, respectively. The mAbs bound independently of each other, i.e. a sample bound one mAb most strongly while another sample with similar affinity strongest bound another mAb. The intensity of binding to sections did not significantly correlate with the serum level of HE4 except for mAb 14E2, but there was a significant correlation between HE4 expression and its detection in supernatants of cultured ovarian carcinomas. CONCLUSIONS HE4 epitopes are expressed independently of each other and their expression of HE4 by cultured ovarian carcinoma cells correlates with the release of HE4 into culture supernatants. he epitope recognized by mAb 14E2 was significantly more expressed by platinum resistant tumors. IMPACT Expression of HE4 by most ovarian carcinomas makes it an excellent biomarker.. Further studies are needed to investigate the clinical relevance of overexpression of a particular epitope.
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Marcišauskas S, Ulfenborg B, Kristjansdottir B, Waldemarson S, Sundfeldt K. Univariate and classification analysis reveals potential diagnostic biomarkers for early stage ovarian cancer Type 1 and Type 2. J Proteomics 2019; 196:57-68. [PMID: 30710757 DOI: 10.1016/j.jprot.2019.01.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 12/13/2018] [Accepted: 01/28/2019] [Indexed: 12/14/2022]
Abstract
Biomarkers for early detection of ovarian tumors are urgently needed. Tumors of the ovary grow within cysts and most are benign. Surgical sampling is the only way to ensure accurate diagnosis, but often leads to morbidity and loss of female hormones. The present study explored the deep proteome in well-defined sets of ovarian tumors, FIGO stage I, Type 1 (low-grade serous, mucinous, endometrioid; n = 9), Type 2 (high-grade serous; n = 9), and benign serous (n = 9) using TMT-LC-MS/MS. Data are available via ProteomeXchange with identifier PXD010939. We evaluated new bioinformatics tools in the discovery phase. This innovative selection process involved different normalizations, a combination of univariate statistics, and logistic model tree and naive Bayes tree classifiers. We identified 142 proteins by this combined approach. One biomarker panel and nine individual proteins were verified in cyst fluid and serum: transaldolase-1, fructose-bisphosphate aldolase A (ALDOA), transketolase, ceruloplasmin, mesothelin, clusterin, tenascin-XB, laminin subunit gamma-1, and mucin-16. Six of the proteins were found significant (p < .05) in cyst fluid while ALDOA was the only protein significant in serum. The biomarker panel achieved ROC AUC 0.96 and 0.57 respectively. We conclude that classification algorithms complement traditional statistical methods by selecting combinations that may be missed by standard univariate tests. SIGNIFICANCE: In the discovery phase, we performed deep proteome analyses of well-defined histology subgroups of ovarian tumor cyst fluids, highly specified for stage and type (histology and grade). We present an original approach to selecting candidate biomarkers combining several normalization strategies, univariate statistics, and machine learning algorithms. The results from validation of selected proteins strengthen our prior proteomic and genomic data suggesting that cyst fluids are better than sera in early stage ovarian cancer diagnostics.
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Affiliation(s)
- Simonas Marcišauskas
- Division of Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Benjamin Ulfenborg
- School of Bioscience, Systems Biology Research Centre, University of Skövde, Skövde, Sweden
| | - Björg Kristjansdottir
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
| | - Sofia Waldemarson
- Department of Immunotechnology, Lund University, Medicon Village, Lund, Sweden
| | - Karin Sundfeldt
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
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Enroth S, Berggrund M, Lycke M, Lundberg M, Assarsson E, Olovsson M, Stålberg K, Sundfeldt K, Gyllensten U. A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer. Clin Proteomics 2018; 15:38. [PMID: 30519148 PMCID: PMC6271635 DOI: 10.1186/s12014-018-9216-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 11/22/2018] [Indexed: 12/11/2022] Open
Abstract
Background Over 500,000 women worldwide are diagnosed with ovarian or endometrial cancer each year. We have used a two-step strategy to identify plasma proteins that could be used to improve the diagnosis of women with an indication of gynecologic tumor and in population screening. Methods In the discovery step we screened 441 proteins in plasma using the proximity extension assay (PEA) and five Olink Multiplex assays (CVD II, CVD III, INF I, ONC II, NEU I) in women with ovarian cancer (n = 106), endometrial cancer (n = 74), benign ovarian tumors (n = 150) and healthy population controls (n = 399). Based on the discovery analyses a set of 27 proteins were selected and two focused multiplex PEA assays were developed. In a replication step the focused assays were used to study an independent set of cases with ovarian cancer (n = 280), endometrial cancer (n = 228), women with benign ovarian tumors (n = 76) and healthy controls (n = 57). Results In the discovery step, 27 proteins that showed an association to cancer status were identified. In the replication analyses, the focused assays distinguished benign tumors from ovarian cancer stage III-IV with a sensitivity of 0.88 and specificity of 0.92 (AUC = 0.92). The assays had a significantly higher AUC for distinguishing benign tumors from late stage ovarian cancer than using CA125 and HE4 (p = 9.56e-22). Also, population controls could be distinguished from ovarian cancer stage III-IV with a sensitivity of 0.85 and a specificity of 0.92 (AUC = 0.89). Conclusion The PEA assays represent useful tools for identification of new biomarkers for gynecologic cancers. The selected protein assays could be used to distinguish benign tumors from ovarian and endometrial cancer in women diagnosed with an unknown suspicious pelvic mass. The panels could also be used in population screening, for identification of women in need of specialized gynecologic transvaginal ultrasound examination. Funding The Swedish Cancer Foundation, Vinnova (SWELIFE), The Foundation for Strategic Research (SSF), Assar Gabrielsson Foundation.
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Affiliation(s)
- Stefan Enroth
- 1Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Uppsala University, Box 815, 75108 Uppsala, Sweden
| | - Malin Berggrund
- 1Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Uppsala University, Box 815, 75108 Uppsala, Sweden
| | - Maria Lycke
- 4Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden
| | - Martin Lundberg
- OLINK Proteomics, Uppsala Science Park, 75183 Uppsala, Sweden
| | - Erika Assarsson
- OLINK Proteomics, Uppsala Science Park, 75183 Uppsala, Sweden
| | - Matts Olovsson
- 3Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Karin Stålberg
- 3Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Karin Sundfeldt
- 4Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden
| | - Ulf Gyllensten
- 1Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Uppsala University, Box 815, 75108 Uppsala, Sweden
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Evaluation of Serum HE4 in Ovarian Tumors, Its Comparison with Serum CA125 and Correlation with Histological Subtypes. INDIAN JOURNAL OF GYNECOLOGIC ONCOLOGY 2018. [DOI: 10.1007/s40944-018-0232-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Belczacka I, Pejchinovski M, Krochmal M, Magalhães P, Frantzi M, Mullen W, Vlahou A, Mischak H, Jankowski V. Urinary Glycopeptide Analysis for the Investigation of Novel Biomarkers. Proteomics Clin Appl 2018; 13:e1800111. [PMID: 30334612 DOI: 10.1002/prca.201800111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/16/2018] [Indexed: 12/20/2022]
Abstract
PURPOSE Urine is a rich source of potential biomarkers, including glycoproteins. Glycoproteomic analysis remains difficult due to the high heterogeneity of glycans. Nevertheless, recent advances in glycoproteomics software solutions facilitate glycopeptide identification and characterization. The aim is to investigate intact glycopeptides in the urinary peptide profiles of normal subjects using a novel PTM-centric software-Byonic. EXPERIMENTAL DESIGN The urinary peptide profiles of 238 normal subjects, previously analyzed using CE-MS and CE-MS/MS and/or LC-MS/MS, are subjected to glycopeptide analysis. Additionally, glycopeptide distribution is assessed in a set of 969 patients with five different cancer types: bladder, prostate and pancreatic cancer, cholangiocarcinoma, and renal cell carcinoma. RESULTS A total of 37 intact O-glycopeptides and 23 intact N-glycopeptides are identified in the urinary profiles of 238 normal subjects. Among the most commonly identified O-glycoproteins are Apolipoprotein C-III and insulin-like growth factor II, while titin among the N-glycoproteins. Further statistical analysis reveals that three O-glycopeptides and five N-glycopeptides differed significantly in their abundance among the different cancer types, comparing to normal subjects. CONCLUSIONS AND CLINICAL RELEVANCE Through the established glycoproteomics workflow, intact O- and N-glycopeptides in human urine are identified and characterized, providing novel insights for further exploration of the glycoproteome with respect to specific diseases.
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Affiliation(s)
- Iwona Belczacka
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany.,University Hospital RWTH Aachen, Institute for Molecular Cardiovascular Research (IMCAR), 52074 Aachen, Germany
| | | | | | | | | | - William Mullen
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, G128QQ Glasgow, UK
| | - Antonia Vlahou
- Biotechnology Division, Biomedical Research Foundation Academy of Athens (BRFAA), 11527 Athens, Greece
| | | | - Vera Jankowski
- University Hospital RWTH Aachen, Institute for Molecular Cardiovascular Research (IMCAR), 52074 Aachen, Germany
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Mi D, Zhang Y. Diagnostic and prognostic value of HE4 in female patients with primary peritoneal carcinoma. Int J Biol Markers 2018; 33:1724600818796595. [PMID: 30238835 DOI: 10.1177/1724600818796595] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND HE4 is a useful tumor marker for the diagnosis of ovarian, endometrial, and fallopian tube carcinoma. AIM The aim of our study was to investigate the value of serum HE4 compared with CA125 in the diagnosis of primary peritoneal carcinoma and the estimation of treatment response and recurrence. METHODS Serum HE4 and CA125 concentrations were measured in both primary peritoneal carcinoma patients and benign gynecological disease controls. The treatment response and recurrence were assessed by serum HE4 and CA125 levels in primary peritoneal carcinoma patients. RESULTS Serum HE4 and CA125 levels were significantly increased in primary peritoneal carcinoma patients compared with benign disease controls ( P<0.001). Compared with CA125, HE4 had lower sensitivity (84.2% vs. 94.7%), but higher specificity (99.2% vs. 85.3%); the combination of HE4 and CA125 led to higher sensitivity and specificity. In the receiver operating characteristic analysis, the area under the curve was 0.956 for HE4, for CA125 was 0.953, for HE4+CA125 was 0.979. Furthermore, HE4 and CA125 were closely associated with treatment response, and our results indicated that primary peritoneal carcinoma patients displayed a larger drop of HE4 compared with CA125 (75.8% vs. 61.5%). Combined with CA125, HE4 elevation better predicted recurrence in primary peritoneal carcinoma patients during the remission period after treatment. CONCLUSIONS This study indicated that the detection of serum HE4 changes may enhance the effectiveness for detecting primary peritoneal carcinoma and estimating the outcome of treatment and recurrence in female primary peritoneal carcinoma patients.
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Affiliation(s)
- Dong Mi
- Department of Clinical Laboratory, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Yuexiang Zhang
- Department of Clinical Laboratory, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
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Palomar Muñoz A, Cordero García JM, Talavera Rubio MDP, García Vicente AM, Pena Pardo FJ, Jiménez Londoño GA, Soriano Castrejón Á, Aranda Aguilar E. Value of [18F]FDG-PET/CT and CA125, serum levels and kinetic parameters, in early detection of ovarian cancer recurrence: Influence of histological subtypes and tumor stages. Medicine (Baltimore) 2018; 97:e0098. [PMID: 29702969 PMCID: PMC5944512 DOI: 10.1097/md.0000000000010098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
To assess the diagnostic accuracy of CA125, its kinetic values and positron emission tomography/computed tomography with 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG-PET/CT), in relation with tumor characteristics for suspected recurrence of ovarian cancer. To evaluate the performance of CA125-related parameters as a selection criteria to perform a [F]FDG-PET/CT.A retrospective analysis of 69 [F]FDG-PET/CT for suspected recurrence of ovarian cancer was performed. All patients had 2 measurements of CA125, before PET/CT, to calculate kinetic values, as CA125vel (CA125vel = [CA125a - CA125b]/time) and CA125dt (CA125dt = [log2 × time]/[logCA125a - CA125b]). Maximum standard uptake value (SUVmax) was calculated. The diagnostic accuracy was calculated for all the variables and the optimal cut-off value of each of them by the receiver-operating characteristics (ROC) analysis. All the tests were compared with tumor characteristics and clinical-radiological evolution during follow-up of at least 6 months.Fifty-five cases were diagnosed of recurrence (11 with CA125 <35 U/mL), while 14 showed no disease (11 with CA125 < 35 U/mL). All of them were correctly cataloged by PET/CT. CA125, CA125vel, and SUVmax showed higher levels in recurrent patients (mean 129.54 U/mL, 24.58 U/mL per mo, and 8.69 g/mL, respectively) than in nonrecurrent (mean 20.35 U/mL, 0.60 U/mL per mo, and 0.64 g/mL, respectively). No statistical differences in CA125dt were found. Patients with recurrence of high-grade serous carcinoma (HGSC) showed higher CA125 and CA125vel, without differences in the rest of subtypes and International Federation of Gynecology and Obstetrics stages. The ROC analyses for CA125, CA125vel, and CA125dt showed an area under the curve (AUC) of 0.873 (95% confidence interval [CI] 0.77-0.969), 0.903 (95% CI 0.813-0.994), and 0.727 (95% CI 0.542-0.913), respectively, with an optimal cut-off point of 23.95 U/mL, 4.49 U/mL per mo, and 3.36 months, respectively, while for the SUVmax the AUC was of 0.982 (95% CI 0.948-1.000), and the cut-off point of 2. Multivariate regression analysis identified CA125 and CA125vel as predictors of recurrence.[F]FDG-PET/CT is more accurate than the parameters obtained from the CA125 to detect early recurrence. CA125vel is the most suitable parameter, mainly in HGSC. Levels of CA125vel ≥ 4.49 U/mL per mo facilitate earlier detection by the execution of a [F]FDG-PET/CT. The calculation of these parameters is independent of tumor stage at diagnosis.
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Affiliation(s)
- Azahara Palomar Muñoz
- Nuclear Medicine-PET IDI Department, Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat (Barcelona)
- Nuclear Medicine Department, Hospital General Universitario de Ciudad Real, Ciudad Real
| | | | | | - Ana Mª García Vicente
- Nuclear Medicine Department, Hospital General Universitario de Ciudad Real, Ciudad Real
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Urinary CE-MS peptide marker pattern for detection of solid tumors. Sci Rep 2018; 8:5227. [PMID: 29588543 PMCID: PMC5869723 DOI: 10.1038/s41598-018-23585-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 03/09/2018] [Indexed: 01/06/2023] Open
Abstract
Urinary profiling datasets, previously acquired by capillary electrophoresis coupled to mass-spectrometry were investigated to identify a general urinary marker pattern for detection of solid tumors by targeting common systemic events associated with tumor-related inflammation. A total of 2,055 urinary profiles were analyzed, derived from a) a cancer group of patients (n = 969) with bladder, prostate, and pancreatic cancers, renal cell carcinoma, and cholangiocarcinoma and b) a control group of patients with benign diseases (n = 556), inflammatory diseases (n = 199) and healthy individuals (n = 331). Statistical analysis was conducted in a discovery set of 676 cancer cases and 744 controls. 193 peptides differing at statistically significant levels between cases and controls were selected and combined to a multi-dimensional marker pattern using support vector machine algorithms. Independent validation in a set of 635 patients (293 cancer cases and 342 controls) showed an AUC of 0.82. Inclusion of age as independent variable, significantly increased the AUC value to 0.85. Among the identified peptides were mucins, fibrinogen and collagen fragments. Further studies are planned to assess the pattern value to monitor patients for tumor recurrence. In this proof-of-concept study, a general tumor marker pattern was developed to detect cancer based on shared biomarkers, likely indicative of cancer-related features.
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39
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Cadkova M, Kovarova A, Dvorakova V, Metelka R, Bilkova Z, Korecka L. Electrochemical quantum dots-based magneto-immunoassay for detection of HE4 protein on metal film-modified screen-printed carbon electrodes. Talanta 2018; 182:111-115. [PMID: 29501129 DOI: 10.1016/j.talanta.2018.01.054] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 01/18/2018] [Accepted: 01/20/2018] [Indexed: 12/19/2022]
Abstract
A novel enzyme-free electrochemical immunosensor was developed for highly sensitive detection and quantification of human epididymis protein 4 (HE4) in human serum. For the first time, core/shell CdSe/ZnS quantum dots were conjugated with anti-HE4 IgG antibodies for subsequent sandwich-type immunosensing with superparamagnetic microparticles functionalized with anti-HE4 IgG antibodies, which allow rapid and efficient HE4 capture from the sample. Electrochemical detection of anti-HE4 IgG - HE4 - anti-HE4 IgGCdSe/ZnS immunocomplex was performed by recording the current response of Cd(II) ions, released from dissolved quantum dots at screen-printed carbon electrode (SPCE), modified with mercury or bismuth film. The linear range of the detection was from 20 pM to 40 nM with limit of detection of 12 pM using three times the standard deviation of blank criterion at mercury-film SPCE and from 100 pM to 2 nM with limit of detection of 89 pM at bismuth-film SPCE. Proposed electrochemical immunosensor meets the requirements for fast and sensitive quantification of HE4 biomarker in early stage of ovarian cancer and due to the proper sensitivity and specificity presents a promising alternative to enzyme-based probes used routinely in clinical diagnostics.
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Affiliation(s)
- Michaela Cadkova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
| | - Aneta Kovarova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
| | - Veronika Dvorakova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
| | - Radovan Metelka
- Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
| | - Zuzana Bilkova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
| | - Lucie Korecka
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic.
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40
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Boylan KLM, Geschwind K, Koopmeiners JS, Geller MA, Starr TK, Skubitz APN. A multiplex platform for the identification of ovarian cancer biomarkers. Clin Proteomics 2017; 14:34. [PMID: 29051715 PMCID: PMC5634875 DOI: 10.1186/s12014-017-9169-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 09/28/2017] [Indexed: 02/06/2023] Open
Abstract
Background Currently, there are no FDA approved screening tools for detecting early stage ovarian cancer in the general population. Development of a biomarker-based assay for early detection would significantly improve the survival of ovarian cancer patients.
Methods We used a multiplex approach to identify protein biomarkers for detecting early stage ovarian cancer. This new technology (Proseek® Multiplex Oncology Plates) can simultaneously measure the expression of 92 proteins in serum based on a proximity extension assay. We analyzed serum samples from 81 women representing healthy, benign pathology, early, and advanced stage serous ovarian cancer patients.
Results Principle component analysis and unsupervised hierarchical clustering separated patients into cancer versus non-cancer subgroups. Data from the Proseek® plate for CA125 levels exhibited a strong correlation with current clinical assays for CA125 (correlation coefficient of 0.89, 95% CI 0.83, 0.93). CA125 and HE4 were present at very low levels in healthy controls and benign cases, while higher levels were found in early stage cases, with highest levels found in the advanced stage cases. Overall, significant trends were observed for 38 of the 92 proteins (p < 0.001), many of which are novel candidate serum biomarkers for ovarian cancer. The area under the ROC curve (AUC) for CA125 was 0.98 and the AUC for HE4 was 0.85 when comparing early stage ovarian cancer versus healthy controls. In total, 23 proteins had an estimated AUC of 0.7 or greater. Using a naïve Bayes classifier that combined 12 proteins, we improved the sensitivity corresponding to 95% specificity from 93 to 95% when compared to CA125 alone. Although small, a 2% increase would have a significant effect on the number of women correctly identified when screening a large population. Conclusions These data demonstrate that the Proseek® technology can replicate the results established by conventional clinical assays for known biomarkers, identify new candidate biomarkers, and improve the sensitivity and specificity of CA125 alone. Additional studies using a larger cohort of patients will allow for validation of these biomarkers and lead to the development of a screening tool for detecting early stage ovarian cancer in the general population. Electronic supplementary material The online version of this article (doi:10.1186/s12014-017-9169-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kristin L M Boylan
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, MMC 395, 420 Delaware Street, S.E, Minneapolis, MN 55455 USA.,Ovarian Cancer Early Detection Program, University of Minnesota, Minneapolis, MN USA
| | - Kate Geschwind
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, MMC 395, 420 Delaware Street, S.E, Minneapolis, MN 55455 USA.,Ovarian Cancer Early Detection Program, University of Minnesota, Minneapolis, MN USA
| | - Joseph S Koopmeiners
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN USA
| | - Melissa A Geller
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN USA
| | - Timothy K Starr
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN USA.,Department of Genetics, Cell Biology and Genetics, University of Minnesota, Minneapolis, MN USA
| | - Amy P N Skubitz
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, MMC 395, 420 Delaware Street, S.E, Minneapolis, MN 55455 USA.,Ovarian Cancer Early Detection Program, University of Minnesota, Minneapolis, MN USA.,Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, MN USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN USA
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Zhong H, Qian Y, Fang S, Yang L, Li L, Gu W. HE4 expression in lung cancer, a meta-analysis. Clin Chim Acta 2017; 470:109-114. [PMID: 28499820 DOI: 10.1016/j.cca.2017.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 05/04/2017] [Accepted: 05/06/2017] [Indexed: 01/11/2023]
Abstract
BACKGROUND The prognostic role of Human epididymis protein 4 (HE4) expression in lung cancer remains controversial. We performed this meta-analysis to assess the prognostic value of HE4 expression in lung cancer. METHODS A systematic literature search was conducted to identify eligible studies in PubMed, Embase and Wanfang databases. The pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were used to assess the relationship. RESULTS A total of 1412 patients from 8 studies were included in this meta-analysis. The results of univariate analysis (HR=1.73, 95% CI: 1.19-2.52, P=0.004) and multivariate analysis (HR=2.49, 95% CI: 1.89-3.28, P<0.001) demonstrated that high HE4 expression in lung cancer patients was correlated with poor overall survival (OS). We observed through further stratified analysis of the results of the univariate analysis that high HE4 expression was associated with worse OS in Asian lung cancer patients (HR=2.48, 95% CI: 1.88-3.26, P<0.001). However, there was no significant association between high HE4 expression and poor OS in Caucasian patients (HR=1.12, 95% CI: 0.80-1.55, P=0.513). CONCLUSION High serum HE4 level was a marker of poor prognosis in lung cancer patients, particularly in Asian patients with lung cancer.
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Affiliation(s)
- Hai Zhong
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Yingying Qian
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Surong Fang
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Linfei Yang
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Lingzhi Li
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China
| | - Wei Gu
- Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People's Republic of China.
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Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b. BMC Cancer 2017; 17:303. [PMID: 28464843 PMCID: PMC5414119 DOI: 10.1186/s12885-017-3289-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 04/24/2017] [Indexed: 11/10/2022] Open
Abstract
Background To characterize the expression of the membrane transporter NaPi2b and antigen targeted by the MX35 antibody in ovarian tumor samples. The current interest to develop monoclonal antibody based therapy of ovarian cancer by targeting NaPi2b emphasizes the need for detailed knowledge and characterization of the expression pattern of this protein. For the majority of patients with ovarian carcinoma the risk of being diagnosed in late stages with extensive loco-regional spread disease is substantial, which stresses the need to develop improved therapeutic agents. Methods The gene and protein expression of SLC34A2/NaPi2b were analyzed in ovarian carcinoma tissues by QPCR (n = 73) and immunohistochemistry (n = 136). The expression levels and antigen localization were established and compared to the tumor characteristics and clinical data. Results Positive staining for the target protein, NaPi2b was detected for 93% of the malignant samples, and we identified three separate distribution patterns of the antigen within the tumors, based on the localization of NaPi2b. There were differences in the staining intensity as well as the distribution pattern when comparing the tumor grade and histology, the mucinous tumors presented a significantly lower expression of both the targeted protein and its related gene. Conclusion Our study identified differences regarding the level of the antigen expression between tumor grade and histology. We have identified differences in the antigen localization between borderline tumors, type 1 and type 2 tumors, and suggest that a pathological evaluation of NaPi2b in the tumors would be helpful in order to know which patients that would benefit from this targeted therapy.
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Terry KL, Schock H, Fortner RT, Hüsing A, Fichorova RN, Yamamoto HS, Vitonis AF, Johnson T, Overvad K, Tjønneland A, Boutron-Ruault MC, Mesrine S, Severi G, Dossus L, Rinaldi S, Boeing H, Benetou V, Lagiou P, Trichopoulou A, Krogh V, Kuhn E, Panico S, Bueno-de-Mesquita HB, Onland-Moret NC, Peeters PH, Gram IT, Weiderpass E, Duell EJ, Sanchez MJ, Ardanaz E, Etxezarreta N, Navarro C, Idahl A, Lundin E, Jirström K, Manjer J, Wareham NJ, Khaw KT, Byrne KS, Travis RC, Gunter MJ, Merritt MA, Riboli E, Cramer DW, Kaaks R. A Prospective Evaluation of Early Detection Biomarkers for Ovarian Cancer in the European EPIC Cohort. Clin Cancer Res 2016; 22:4664-75. [PMID: 27060155 PMCID: PMC5026545 DOI: 10.1158/1078-0432.ccr-16-0316] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 03/21/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study. EXPERIMENTAL DESIGN We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis. RESULTS We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker. CONCLUSIONS CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 4664-75. ©2016 AACRSee related commentary by Skates, p. 4542.
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Affiliation(s)
- Kathryn L Terry
- Ob/Gyn Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts. Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts.
| | - Helena Schock
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Renée T Fortner
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anika Hüsing
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Raina N Fichorova
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts. Genital Tract Biology Laboratory, Brigham and Women's Hospital, Boston, Massachusetts
| | - Hidemi S Yamamoto
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts. Genital Tract Biology Laboratory, Brigham and Women's Hospital, Boston, Massachusetts
| | - Allison F Vitonis
- Ob/Gyn Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts
| | - Theron Johnson
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kim Overvad
- Department of Epidemiology, Aarhus University, Aarhus, Denmark
| | | | - Marie-Christine Boutron-Ruault
- Université Paris-Sud, Centre de recherche en Épidémiologie et Santé des Populations (CESP), Institut Nationale de Santë et de Recherche Médicale (INSERM), Villejuif, France. Gustave Roussy, Villejuif, France
| | - Sylvie Mesrine
- Université Paris-Sud, Centre de recherche en Épidémiologie et Santé des Populations (CESP), Institut Nationale de Santë et de Recherche Médicale (INSERM), Villejuif, France. Gustave Roussy, Villejuif, France
| | - Gianluca Severi
- Université Paris-Sud, Centre de recherche en Épidémiologie et Santé des Populations (CESP), Institut Nationale de Santë et de Recherche Médicale (INSERM), Villejuif, France. Gustave Roussy, Villejuif, France. Human Genetics Foundation (HuGeF), Torino, Italy. Cancer Council Victoria and University of Melbourne, Australia
| | - Laure Dossus
- Nutrition and Metabolism Section, International Agency for Research on Cancer, Lyon, France
| | - Sabina Rinaldi
- Nutrition and Metabolism Section, International Agency for Research on Cancer, Lyon, France
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany
| | - Vassiliki Benetou
- Helenic Health Foundation Athens, Athens, Greece. WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - Pagona Lagiou
- Helenic Health Foundation Athens, Athens, Greece. WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - Antonia Trichopoulou
- Helenic Health Foundation Athens, Athens, Greece. WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - Vittorio Krogh
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Elisabetta Kuhn
- Department of Morphology, Surgery and Experimental Medicine and Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA) Centre, University of Ferrara, Ferrara, Italy
| | - Salvatore Panico
- Dipartimento di Medicina Clinical e Chirurgia, Federico II University, Naples, Italy
| | | | - N Charlotte Onland-Moret
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Petra H Peeters
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Inger Torhild Gram
- Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Elisabete Weiderpass
- Department of Community Medicine, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. Department of Research, Cancer Registry of Norway, Institute of Population-Based Case Research, Oslo, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland
| | - Eric J Duell
- Unit of Nutrition and Cancer Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona, Spain
| | - Maria-Jose Sanchez
- Escuela Andaluza de Salud Publica, Instituto de Investigación Bionsanitaria ibs. Granada, Hospitales Universitarios de Granada, Granada, Spain. Centro de Investigación Biomédica En Red (CIBER), Section Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Eva Ardanaz
- Centro de Investigación Biomédica En Red (CIBER), Section Epidemiology and Public Health (CIBERESP), Madrid, Spain. Navarra Public Health Institute, Pamplona, Spain. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Nerea Etxezarreta
- Centro de Investigación Biomédica En Red (CIBER), Section Epidemiology and Public Health (CIBERESP), Madrid, Spain. Public Health Division of Gipuzkoa, Regional Government of the Basque Country, Basque, Spain
| | - Carmen Navarro
- Centro de Investigación Biomédica En Red (CIBER), Section Epidemiology and Public Health (CIBERESP), Madrid, Spain. Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain. Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain
| | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology Umeå, University of Umeå, Umeå, Sweden
| | - Eva Lundin
- Department of Medical Biosciences, Pathology Umeå, University of Umeå, Umeå, Sweden
| | - Karin Jirström
- Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden. Department of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Jonas Manjer
- Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden. Department of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Nicholas J Wareham
- Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
| | - Kay-Tee Khaw
- Clinical Gerontology, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - Karl Smith Byrne
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College of London, London, United Kingdom
| | - Melissa A Merritt
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College of London, London, United Kingdom
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College of London, London, United Kingdom
| | - Daniel W Cramer
- Ob/Gyn Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts
| | - Rudolf Kaaks
- Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts.
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Diagnostic Value of HE4 in Distinguishing Malignant from Benign Pelvic Masses. INDIAN JOURNAL OF GYNECOLOGIC ONCOLOGY 2016. [DOI: 10.1007/s40944-016-0079-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Yu S, Lee JK, Kim JH, Park H, Lee MY, Ryu S, Kwon MJ, Woo HY. Diagnostic performance and establishment of reference limits of HE4 in Korean healthy women. Gynecol Oncol 2016; 143:128-134. [PMID: 27426308 DOI: 10.1016/j.ygyno.2016.07.100] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 06/27/2016] [Accepted: 07/10/2016] [Indexed: 11/20/2022]
Abstract
OBJECTIVE We aimed to establish distribution and reference limits of HE4 and risk of ovarian malignancy algorithm (ROMA) in healthy Korean women and investigated the factors influencing HE4 levels. We also investigated the diagnostic performances of HE4 and ROMA score, compared with CA125. METHODS We collected specimens from 1809 healthy Korean women, 140 specimens from patients with ovarian cancers (OCs) and 123 specimens from patients with benign ovarian tumor. Serum HE4 and CA125 concentrations were measured using an electrochemiluminescence immunoassay. The receiver operator characteristic (ROC) curve analysis was done for ROMA, HE4, CA125 and combining of HE4 and CA125. RESULTS HE4 level was influenced by age, not by menopausal status. The 97.5th percentile upper reference limit of HE4 of subjects <50years and ≥50year-old was 63.87pmol/L and 88.28pmol/L, respectively. The 97.5th percentile upper reference limits of ROMA score were 13.66 in premenopausal and 19.30 in postmenopausal women. The serum HE4 level was even lower in the patients with benign tumor compared to those in healthy controls. HE4 had significantly higher concentrations in OCs than benign ovarian tumor (P<0.001). ROMA and HE4 combined with CA125 or not performed better diagnostically than CA125 alone for distinguishing OCs, with AUCs of 0.844 for ROMA, 0.827 for combining of HE4 and CA125, 0.825 for HE4, and 0.795 for CA125. CONCLUSIONS The reference limit of HE4 was different from those reported by other studies, suggesting racial or regional difference. HE4 and ROMA were better than CA125 for differentiation normal and benign ovarian tumor from OCs. (Word count: 253).
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Affiliation(s)
- Shinae Yu
- Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin Kyung Lee
- KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Jae-Hoon Kim
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyosoon Park
- Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Mi Yeon Lee
- Department of Biostatistics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seungho Ryu
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Min-Jung Kwon
- Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Hee-Yeon Woo
- Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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The Value of Serum CA125 in the Diagnosis of Borderline Tumors of the Ovary: A Subanalysis of the Prospective Multicenter ROBOT Study. Int J Gynecol Cancer 2016; 25:1248-52. [PMID: 25978292 DOI: 10.1097/igc.0000000000000476] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE The value of the serum tumor marker CA125 in borderline tumors of the ovary (BOTs) is not well defined, with unclear benefit in both diagnosis and follow-up. The aim of the present project was to identify the predictive value of CA125 for stage and relapse. METHODS CA125 data were extracted from the ROBOT multicenter study of patients with BOT treated between 1998 and 2008 in 24 German centers. While patients' data were retrieved retrospectively from hospital records and clinical tumor registries, follow-up and independent central pathology review were performed prospectively. RESULTS We identified 127 patients from the ROBOT database fulfilling the eligibility criterion of available CA125 at initial diagnosis. Eighty-three (65.3%) patients had increased CA125 levels (>35 U/L). Of the patients, 85.0% presented with serous and 13.4% with mucinous BOT histology, whereas 29.9% had stage I disease. Fifteen (11.8%) patients experienced a relapse. Multivariate analysis identified raised CA125, young age, and serous histology as independent predictors of peritoneal implants of any type at initial presentation. Raised CA125 at initial diagnosis was, however, not an independent predictor of future relapse. DISCUSSION Elevated CA125 seems to be associated with the presence of peritoneal implants of any type at initial diagnosis of serous BOT, but failed to have any independent predictive value on future relapse. Prospective multicenter studies are warranted to evaluate CA125 measurements in the follow-up management of BOT.
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Mi D, Zhang YX, Wang CJ, Feng Q, Qi P, Chen SQ. Diagnostic and prognostic value of serum human epididymis protein 4 in patients with primary fallopian tube carcinoma. J Obstet Gynaecol Res 2016; 42:1326-1335. [PMID: 27307153 DOI: 10.1111/jog.13053] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 04/09/2016] [Indexed: 01/01/2023]
Abstract
AIM The aim of our study was to assess the levels of human epididymis protein 4 (HE4) with the common tumor marker carbohydrate antigen 125 (CA125) in the diagnosis and monitoring of therapy for primary fallopian tube carcinoma (PFTC). METHODS Serum HE4 and CA125 levels from 82 PFTC patients and 154 patients with benign pelvic masses as the control were measured by Roche electrochemiluminescent immunoassay. HE4 determinations for surgery response and recurrence monitoring were assessed in PFTC patients. RESULTS Serum HE4 and CA125 concentrations were significantly higher in PFTC patients compared with those seen in patients with benign pelvic masses (P < 0.001). Compared with CA125, HE4 had higher specificity, but lower sensitivity whether at early or advanced stage, and the combination of HE4 + CA125 led to higher sensitivity and specificity. HE4 + CA125 performed significantly better than CA125 or HE4 alone in early stage patients. In early stage the sensitivity was 35.7% for HE4 and 64.3% for CA125, while sensitivity for the combination of HE4 and CA125 could reach 71.4%. Furthermore, the two markers were associated with the progression and histology of PFTC. Serum HE4 level was closely correlated with surgical therapy. PFTC patients displayed a greater decline in the level of HE4 compared with CA125 (76.4% vs 55.7%). Combined with CA125, HE4 elevation better predicted recurrence in PFTC patients. CONCLUSIONS This study indicated that serum HE4 levels are closely associated with PFTC and the outcome of surgical therapy and recurrence in Chinese patients.
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Affiliation(s)
- Dong Mi
- Department of Clinical Laboratory, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China.
| | - Yue-Xiang Zhang
- Department of Clinical Laboratory, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Cheng-Jin Wang
- Department of Clinical Laboratory, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Qiang Feng
- Department of Clinical Laboratory, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Pei Qi
- Department of Clinical Laboratory, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Shu-Qin Chen
- Department of Clinical Laboratory, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
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Čadková M, Dvořáková V, Metelka R, Bílková Z, Korecká L. Alkaline phosphatase labeled antibody-based electrochemical biosensor for sensitive HE4 tumor marker detection. Electrochem commun 2015. [DOI: 10.1016/j.elecom.2015.06.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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Jia LT, Zhang YC, Li J, Tian Y, Li JF. The role of human epididymis protein 4 in the diagnosis of epithelial ovarian cancer. Clin Transl Oncol 2015. [PMID: 26220095 DOI: 10.1007/s12094-015-1365-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE Epithelial ovarian cancer is one of the most lethal female genital tract cancers. Early diagnosis of EOC would benefit the patients a lot. Human epididymis protein 4 (HE4) has been regarded as a new powerful biomarker in diagnosis of EOC; we hope to obtain system knowledge of HE4 and understand the role of HE4 in diagnosis of epithelial ovarian cancer (EOC). METHODS We searched Pubmed, Embase, Medline, and Chinese National Knowledge Infrastructure (CNKI) for articles that included HE4's origin, characteristics, detection methods, clinical efficacy alone or combined with CA125, the risk of malignancy index, and the risk of ovarian malignancy algorithm. The diagnostic performance for the EOC and the role in the recurrence and procession in EOC were also discussed. RESULTS We got 83 most related articles and found that there were significantly difference existing among the studies, such as the clinical characteristics of patients, the methodology for measuring HE4, the different cut-offs for HE4 and so on. CONCLUSION HE4 is a promising biomarker for the early diagnosis of EOC. However, each lab should establish its own reference internal of HE4.
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Affiliation(s)
- L-T Jia
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Kangfuqian Street 7, Zhengzhou, 450052, People's Republic of China.
| | - Y-C Zhang
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Kangfuqian Street 7, Zhengzhou, 450052, People's Republic of China
| | - J Li
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Kangfuqian Street 7, Zhengzhou, 450052, People's Republic of China
| | - Y Tian
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Kangfuqian Street 7, Zhengzhou, 450052, People's Republic of China
| | - J-F Li
- Department of Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, Kangfuqian Street 7, Zhengzhou, 450052, People's Republic of China
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Vitiazeva V, Kattla JJ, Flowers SA, Lindén SK, Premaratne P, Weijdegård B, Sundfeldt K, Karlsson NG. The O-Linked Glycome and Blood Group Antigens ABO on Mucin-Type Glycoproteins in Mucinous and Serous Epithelial Ovarian Tumors. PLoS One 2015; 10:e0130197. [PMID: 26075384 PMCID: PMC4468167 DOI: 10.1371/journal.pone.0130197] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 05/16/2015] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Mucins are heavily O-glycosylated proteins where the glycosylation has been shown to play an important role in cancer. Normal epithelial ovarian cells do not express secreted mucins, but their abnormal expression has previously been described in epithelial ovarian cancer and may relate to tumor formation and progression. The cyst fluids were shown to be a rich source for acidic glycoproteins. The study of these proteins can potentially lead to the identification of more effective biomarkers for ovarian cancer. METHODS In this study, we analyzed the expression of the MUC5AC and the O-glycosylation of acidic glycoproteins secreted into ovarian cyst fluids. The samples were obtained from patients with serous and mucinous ovarian tumors of different stages (benign, borderline, malignant) and grades. The O-linked oligosaccharides were released and analyzed by negative-ion graphitized carbon Liquid Chromatography (LC) coupled to Electrospray Ionization tandem Mass Spectrometry (ESI-MSn). The LC-ESI-MSn of the oligosaccharides from ovarian cyst fluids displayed differences in expression of fucose containing structures such as blood group ABO antigens and Lewis-type epitopes. RESULTS The obtained data showed that serous and mucinous benign adenomas, mucinous low malignant potential carcinomas (LMPs, borderline) and mucinous low-grade carcinomas have a high level of blood groups and Lewis type epitopes. In contrast, this type of fucosylated structures were low abundant in the high-grade mucinous carcinomas or in serous carcinomas. In addition, the ovarian tumors that showed a high level of expression of blood group antigens also revealed a strong reactivity towards the MUC5AC antibody. To visualize the differences between serous and mucinous ovarian tumors based on the O-glycosylation, a hierarchical cluster analysis was performed using mass spectrometry average compositions (MSAC). CONCLUSION Mucinous benign and LMPs along with mucinous low-grade carcinomas appear to be different from serous and high-grade mucinous carcinomas based on their O-glycan profiles.
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Affiliation(s)
- Varvara Vitiazeva
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
- * E-mail:
| | - Jayesh J. Kattla
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Sarah A. Flowers
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Sara K. Lindén
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Pushpa Premaratne
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Birgitta Weijdegård
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
| | - Karin Sundfeldt
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden
| | - Niclas G. Karlsson
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
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