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Kim H, Lee J, Park MR, Choi Z, Han SJ, Kim D, Shin S, Lee ST, Choi JR, Park SW. Prognostic Value of Residual Circulating Tumor DNA in Metastatic Pancreatic Ductal Adenocarcinoma. Ann Lab Med 2025; 45:199-208. [PMID: 39801270 PMCID: PMC11788705 DOI: 10.3343/alm.2024.0345] [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: 07/04/2024] [Revised: 10/12/2024] [Accepted: 12/20/2024] [Indexed: 01/24/2025] Open
Abstract
Background Circulating tumor DNA (ctDNA) is a potential biomarker in pancreatic ductal adenocarcinoma (PDAC). However, studies on residual ctDNA in patients post-chemotherapy are limited. We assessed the prognostic value of residual ctDNA in metastatic PDAC relative to that of carbohydrate antigen 19-9 (CA19-9). Methods ctDNA analysis using a targeted next-generation sequencing panel was performed at baseline and during chemotherapy response evaluation in 53 patients. Progression-free survival (PFS) and overall survival (OS) were first evaluated based on ctDNA positivity at baseline. For further comparison, patients testing ctDNA-positive at baseline were subdivided based on residual ctDNA into ctDNA responders (no residual ctDNA post-chemotherapy) and ctDNA non-responders (residual ctDNA post-chemotherapy). Additional survival analysis was performed based on CA19-9 levels. Results The baseline ctDNA detection rate was 56.6%. Although clinical outcomes tended to be poorer in patients with baseline ctDNA positivity than in those without, the differences were not significant. Residual ctDNA post-chemotherapy was associated with reduced PFS and OS. The prognosis of ctDNA responders was better than that of non-responders but did not significantly differ from that of ctDNA-negative individuals (no ctDNA both at baseline and during post-chemotherapy). Compared with ctDNA responses to chemotherapy, a ≥ 50% decrease in the CA19-9 level had less effect on both PFS and OS based on hazard ratios and significance levels. ctDNA could be monitored in half of the patients whose baseline CA19-9 levels were within the reference range. Conclusions Residual ctDNA analysis post-chemotherapy is a promising approach for predicting the clinical outcomes of patients with metastatic PDAC.
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Affiliation(s)
- Hongkyung Kim
- Department of Laboratory Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jinho Lee
- Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Mi Ri Park
- Department of Laboratory Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | | | | | | | - Saeam Shin
- Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Seung-Tae Lee
- Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
- Dxome Co., Ltd., Seongnam, Korea
| | - Jong Rak Choi
- Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
- Dxome Co., Ltd., Seongnam, Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
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2
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Huang A, Shi J, Sun Z, Yang Y, Gao Z, Gu J. Identification of a prognostic signature and ENTR1 as a prognostic biomarker for colorectal mucinous adenocarcinoma. Front Oncol 2023; 13:1061785. [PMID: 37182178 PMCID: PMC10172661 DOI: 10.3389/fonc.2023.1061785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 04/11/2023] [Indexed: 05/16/2023] Open
Abstract
Background Mucinous adenocarcinoma (MAC) is a unique clinicopathological colorectal cancer (CRC) type that has been recognized as a separate entity from non-mucinous adenocarcinoma (NMAC), with distinct clinical, pathologic, and molecular characteristics. We aimed to construct prognostic signatures and identifying candidate biomarkers for patients with MAC. Methods Differential expression analysis, weighted correlation network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO)-Cox regression model were used to identify hub genes and construct a prognostic signature based on RNA sequencing data from TCGA datasets. The Kaplan-Meier survival curve, gene set enrichment analysis (GSEA), cell stemness, and immune infiltration were analyzed. Biomarker expression in MAC and corresponding normal tissues from patients operated in 2020 was validated using immunohistochemistry. Results We constructed a prognostic signature based on ten hub genes. Patients in the high-risk group had significantly worse overall survival (OS) than patients in the low-risk group (p < 0.0001). We also found that ENTR1 was closely associated with OS (p = 0.016). ENTR1 expression was significantly positively correlated with cell stemness of MAC (p < 0.0001) and CD8+ T cell infiltration (p = 0.01), whereas it was negatively associated with stromal scores (p = 0.03). Finally, the higher expression of ENTR1 in MAC tissues than in normal tissues was validated. Conclusion We established the first MAC prognostic signature, and determined that ENTR1 could serve as a prognostic marker for MAC.
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Affiliation(s)
- An Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jingyi Shi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhuang Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yong Yang
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China
| | - Zhaoya Gao
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Jin Gu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing, China
- Peking Tsinghua Center for Life Science, Peking University International Cancer Center, Beijing, China
- *Correspondence: Jin Gu,
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3
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Shen F, Liu C, Zhang W, He S, Wang F, Wang J, Li Q, Zhou F. Serum levels of IL-6 and CRP can predict the efficacy of mFOLFIRINOX in patients with advanced pancreatic cancer. Front Oncol 2022; 12:964115. [PMID: 35965580 PMCID: PMC9372918 DOI: 10.3389/fonc.2022.964115] [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: 06/08/2022] [Accepted: 07/05/2022] [Indexed: 12/24/2022] Open
Abstract
Objectives There is an urgent need for biomarkers that predict the survival outcome of patients diagnosed with metastatic pancreatic cancer, undergoing systemic chemotherapy. This study aimed to identify biomarkers associated with the survival of mPC patients treated with modified FOLFIRINOX (mFOLFIRINOX) as first-line chemotherapy. Methods This was a retrospective study of 30 patients with mPC who received mFOLFIRINOX between October 2018 and March 2021. Data on carcinoembryonic antigen (CEA), cancer antigen (CA)199, interleukin (IL)-6, C-reactive protein (CRP), neutrophils, platelets, lymphocytes, and albumin were collected and dichotomized using the upper or lower limit, as appropriate. These markers were examined for their association with progression-free survival (PFS). A receiver operating characteristic (ROC) curve analysis was used to explore a suitable model to predict mFOLFIRINOX effectiveness. Results IL-6 and CRP levels were associated with poor progression (P = 0.004 and P = <0.001, respectively) of mPC. The high IL-6 level was an independent poor prognostic factor for PFS (HR=4.66, 95%CI: 1.32-16.37, P=0.016) in the multivariable analysis. Patients with high IL-6 levels had a shorter PFS than those with low IL-6 levels (median PFS: 257 vs. 150 days, P=0.020). An increase in IL-6 and CRP levels during chemotherapy positively correlated with disease progression (P = <0.001 for both). The model combining IL-6 with CRP levels helped predict the outcomes of mPC patients treated with mFOLFIRINOX (AUC: 0.811, 95%CI: 0.639-0.983, P=0.003). Conclusions The serum levels of IL-6 and CRP might be considered as valuable biomarkers in predicting the outcomes of patients with mPC who received the mFOLFIRINOX regimen.
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Affiliation(s)
- Feifei Shen
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chuan Liu
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Weiguo Zhang
- Department of Radiology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Sijia He
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Fan Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jingjue Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qi Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Fei Zhou
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- *Correspondence: Fei Zhou,
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Arivazhagan S, Kantamani D, Tanner NE, Kundranda MN, Stagg MP. Infection Masquerading as Recurrence of Pancreatic Ductal Adenocarcinoma: A Cautionary Tale. Cureus 2021; 13:e17010. [PMID: 34540411 PMCID: PMC8424059 DOI: 10.7759/cureus.17010] [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] [Accepted: 08/08/2021] [Indexed: 11/05/2022] Open
Abstract
We present a case of a 59-year-old male undergoing adjuvant chemotherapy for his pancreatic adenocarcinoma post-surgical resection. He had an acute rise in carbohydrate antigen (CA) 19-9 level, which raised suspicion of metastatic disease. Instead, the patient was diagnosed to have a liver abscess, the treatment of which brought the CA 19-9 level back to normal. Unfortunately, although CA 19-9 is Food and Drug Administration (FDA)-approved tumor marker for pancreatic cancer, it is also elevated in several benign conditions, causing fear of cancer and unnecessary diagnostic workup. Hence, caution is necessary for interpreting the significance of its elevation.
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Affiliation(s)
| | - Deepti Kantamani
- Internal Medicine, Baton Rouge General Medical Center, Baton Rouge, USA
| | | | | | - M Patrick Stagg
- Internal Medicine Residency Program, Baton Rouge General Medical Center, Baton Rouge, USA
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Zhao B, Cheng Q, Cao H, Zhou X, Li T, Dong L, Wang W. Dynamic change of serum CA19-9 levels in benign and malignant patients with obstructive jaundice after biliary drainage and new correction formulas. BMC Cancer 2021; 21:517. [PMID: 33962560 PMCID: PMC8105938 DOI: 10.1186/s12885-021-08204-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 04/16/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND CA19-9 is one of the most widely used tumor markers in biliary-pancreatic diseases. The measured value may not factually reflect the genuine CA19-9 level secreted by tumor, which affected by biliary obstruction. There is an urgent need of developing a correction formula of CA19-9 in biliary obstructive patients to guide clinical practice and avoid making improper clinical decision. METHODS Clinical characteristics were collected among patients undergoing biliary drainage in our hospital between January 2014 and January 2019. By comparing the malignant and benign patients statistically, dynamic change trend of CA19-9 levels after biliary drainage was obtained. The correction formulas of CA19-9 were generated by means of linear regression. RESULTS 121 patients, including 102 malignant and 19 benign patients, were enrolled in this study. The baseline CA19-9 level of malignant patients is much higher than that of benign patients. Total bilirubin (TB) level was found to be not related with CA19-9 value (p = 0.109). The drop proportion of the average CA19-9 level in the malignant patients (39.2%, IQR -18.4-78.6%) was much lower than that in the benign patients (75.7%, IQR 58.1-86.6%) (p = 0.014). The correction formula, CA19-9True = 0.63 × CA19-9Measured - 20.3 (R2 = 0.693, p<0.001), was generated based on the linear relation between CA19-9 after drainage and CA19-9 before drainage in malignant patients, which had similar diagnostic value with true CA19-9 value. CONCLUSIONS Quantitative correction formulas of CA19-9 considering the effect of biliary decompression was first proposed in this study, aiming to provide a more accurate CA19-9 level to make more accurate clinical decision and avoid making improper therapeutic schedule.
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Affiliation(s)
- Bangbo Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Qin Cheng
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Hongtao Cao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Xingtong Zhou
- Department of Brease Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Tianhao Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Liangbo Dong
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Weibin Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
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6
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Kulkarni NM, Soloff EV, Tolat PP, Sangster GP, Fleming JB, Brook OR, Wang ZJ, Hecht EM, Zins M, Bhosale PR, Arif-Tiwari H, Mannelli L, Kambadakone AR, Tamm EP. White paper on pancreatic ductal adenocarcinoma from society of abdominal radiology's disease-focused panel for pancreatic ductal adenocarcinoma: Part I, AJCC staging system, NCCN guidelines, and borderline resectable disease. Abdom Radiol (NY) 2020; 45:716-728. [PMID: 31748823 DOI: 10.1007/s00261-019-02289-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive gastrointestinal malignancy with a poor 5-year survival rate. Accurate staging of PDAC is an important initial step in the development of a stage-specific treatment plan. Different staging systems/consensus statements convened by different societies and academic practices are currently used. The most recent version of the American Joint Committee on Cancer (AJCC) tumor/node/metastases (TNM) staging system for PDAC has shifted its focus from guiding management to assessing prognosis. In order to preoperatively define the resectability of PDAC and to guide management, additional classification systems have been developed. The National Comprehensive Cancer Network (NCCN) guidelines, one of the most commonly used systems, provide recommendations on the management and the determination of resectability for PDAC. The NCCN divides PDAC into three categories of resectability based on tumor-vessel relationship: 'resectable,' 'borderline resectable,' and 'unresectable'. Among these, the borderline disease category is of special interest given its evolution over time and the resulting variations in the definition and the associated recommendations for management between different societies. It is important to be familiar with the evolving criteria, and treatment and follow-up recommendations for PDAC. In this article, the most current AJCC staging (8th edition), NCCN guidelines (version 2.2019-April 9, 2019), and challenges and controversies in borderline resectable PDAC are reviewed.
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Affiliation(s)
- Naveen M Kulkarni
- Department of Radiology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI, 53226, USA.
| | - Erik V Soloff
- Department of Radiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Parag P Tolat
- Department of Radiology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI, 53226, USA
| | - Guillermo P Sangster
- Department of Radiology, LSU Health - Shreveport Ochsner-LSU Health - Shreveport, 1501 Kings Highway, Shreveport, LA, 71103, USA
| | - Jason B Fleming
- Gastrointestinal Oncology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Olga R Brook
- Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Shapiro 4, Boston, MA, 02215-5400, USA
| | - Zhen Jane Wang
- Department of Radiology and Biomedical Imaging, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA
| | - Elizabeth M Hecht
- Department of Radiology, Columbia University Medical Center, 622 W 168th St, PH1-317, New York, NY, 10032, USA
| | - Marc Zins
- Department of Radiology, Groupe Hospitalier Paris Saint-Joseph, 185 Rue Raymond Losserand, 75014, Paris, France
| | - Priya R Bhosale
- Abdominal Imaging Department, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1473, Houston, TX, 77030-400, USA
| | - Hina Arif-Tiwari
- Department of Radiology, University of Arizona College of Medicine, 1501 N. Campbell Ave., P.O. Box 245067, Tucson, AZ, 85724, USA
| | | | - Avinash R Kambadakone
- Department of Radiology, Massachusetts General Hospital, 55 Fruit Street, White 270, Boston, MA, 02114, USA
| | - Eric P Tamm
- Abdominal Imaging Department, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1473, Houston, TX, 77030-400, USA
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7
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Akazawa Y, Mizuno S, Fujinami N, Suzuki T, Yoshioka Y, Ochiya T, Nakamoto Y, Nakatsura T. Usefulness of serum microRNA as a predictive marker of recurrence and prognosis in biliary tract cancer after radical surgery. Sci Rep 2019; 9:5925. [PMID: 30976046 PMCID: PMC6459925 DOI: 10.1038/s41598-019-42392-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 03/20/2019] [Indexed: 02/06/2023] Open
Abstract
Biliary tract cancer (BTC) is an aggressive type of malignant tumour. Even after radical resection, the risk of recurrence is still high, resulting in a poor prognosis. Here, we investigated the usefulness of serum miRNAs as predictive markers of recurrence and prognosis for patients with BTC after radical surgery using 66 serum samples that were collected at three time points from 22 patients with BTC who underwent radical surgery. Using microarray analysis, we successfully identified six specific miRNAs (miR-1225-3p, miR-1234-3p, miR1260b, miR-1470, miR-6834-3p, and miR-6875-5p) associated with recurrence and prognosis of BTC after radical surgery. In addition, using a combination of these miRNAs, we developed a recurrence predictive index to predict recurrence in patients with BTC after operation with high accuracy. Patients having higher index scores (≥ cut-off) had significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with lower index scores (<cut-off). Furthermore, the index was an independent factor related to RFS and OS by univariate and multivariate analyses using a Cox hazard proportional model. Overall, our results provided compelling evidence for the potential usefulness of specific serum miRNAs as effective predictive tools for recurrence and prognosis in patients with BTC who underwent radical surgery.
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Affiliation(s)
- Yu Akazawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Shoichi Mizuno
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Yusuke Yoshioka
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.,Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
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Lu JJ, Yuan Z. Application of DNA methylation in early diagnosis and treatment of pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2019; 27:13-19. [DOI: 10.11569/wcjd.v27.i1.13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most malignant gastrointestinal tumors, characterized by a poor prognosis. Most of the patients have an advanced disease at the time of diagnosis and lose the opportunity of radical surgery, resulting in a 5-year survival rate of less than 5%. Circulating tumor DNA, whose concentration in plasma of patients with pancreatic adenocarcinoma is higher than that in health controls, carries specific gene mutation and aberrant DNA methylation. Epigenetic change is one of the important characteristics of cell carcinogenesis. DNA methylation is an early event in tumorigenesis, which is more helpful for early diagnosis than gene mutation and can be observed in each stage of PC. Therefore, the detection of aberrant DNA methylation in the promoter region in patients with PC may be a non-invasive method for early cancer detection, predicting prognosis, and monitoring recurrence. In the present review, we discuss the recent advances in the study of DNA methylation in the early diagnosis of PC, and the potential application value in the treatment of PC.
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Affiliation(s)
- Jia-Jun Lu
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Zhou Yuan
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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Luo Y, Zhu H, Tan T, He J. Current Standards and Recent Advances in Biomarkers of Major Endocrine Tumors. Front Pharmacol 2018; 9:963. [PMID: 30250431 PMCID: PMC6139354 DOI: 10.3389/fphar.2018.00963] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/03/2018] [Indexed: 12/18/2022] Open
Abstract
The complexity of endocrine tumor diagnosis stems from its variable symptoms and presentation that may mimic many other disease states, or display asymptomatic properties for a prolonged amount of time. Early and accurate disease identification is needed for better patient prognosis. The key to this may be in using validated biomarkers with enhanced sensitivity and specificity. Several biomarkers are consistently used across various endocrine tumor types, possibly indicating a deeper pathophysiological mechanism behind endocrine cancer genesis and development. For example, carbohydrate antigen (CA) is measured in both pancreatic adenocarcinoma as well as ovarian cancer for diagnosis, surveillance, and risk stratification. The discovery of measuring miRNAs that are highly expressed in malignant tumors is also a novel strategy across multiple endocrine tumor types, and is propelling the future advancement of biomarker development. This review introduces currently utilized biomarkers in some of the commonly known endocrine tumors, including thyroid, adrenal, pituitary, pancreatic, and gonadal carcinoma, as well as future research directions.
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Affiliation(s)
- Yanhong Luo
- Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Hua Zhu
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Tao Tan
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jianfeng He
- Children’s Hospital of Chongqing Medical University, Chongqing, China
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10
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Lee JH, Yu SE, Kim KH, Yu MH, Jeong IH, Cho JY, Park SJ, Lee WJ, Han SS, Kim TH, Hong EK, Woo SM, Yoo BC. Individualized metabolic profiling stratifies pancreatic and biliary tract cancer: a useful tool for innovative screening programs and predictive strategies in healthcare. EPMA J 2018; 9:287-297. [PMID: 30174764 PMCID: PMC6107458 DOI: 10.1007/s13167-018-0147-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 07/31/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) and biliary tract cancer (BTC) are highly aggressive cancers, characterized by their rarity, difficulty in diagnosis, and overall poor prognosis. Diagnosis of PC and BTC is complex and is made using a combination of appropriate clinical suspicion, imaging and endoscopic techniques, and cytopathological examination. However, the late-stage detection and poor prognosis of this tumor have led to an urgent need for biomarkers for early and/or predictive diagnosis and improved personalized treatments. WORKING HYPOTHESIS There are two hypotheses for focusing on low-mass metabolites in the blood. First, valuable information can be obtained from the masses and relative amounts of such metabolites, which present as low-mass ions (LMIs) in mass spectra. Second, metabolic profiling of individuals may provide important information regarding biological changes in disease states that is useful for the early diagnosis of PC and BTC. MATERIALS AND METHODS To assess whether profiling metabolites in serum can serve as a non-invasive screening tool for PC and BTC, 320 serum samples were obtained from patients with PC (n = 51), BTC (n = 39), colorectal cancer (CRC) (n = 100), and ovarian cancer (OVC) (n = 30), and from healthy control subjects (control) (n = 100). We obtained information on the relative amounts of metabolites, as LMIs, via triple time-of-flight mass spectrometry. All data were analyzed according to the peak area ratios of discriminative LMIs. RESULTS AND CONCLUSIONS The levels of the 14 discriminative LMIs were higher in the PC and BTC groups than in the control, CRC and OVC groups, but only two LMIs discriminated between PC and BTC: lysophosphatidylcholine (LysoPC) (16:0) and LysoPC(20:4). The levels of these two LysoPCs were also slightly lower in the PC/BTC/CRC/OVC groups compared with the control group. Taken together, the data showed that metabolic profiling can precisely denote the status of cancer, and, thus, could be useful for screening. This study not only details efficient methods to identify discriminative LMIs for cancer screening but also provides an example of metabolic profiling for distinguishing PC from BTC. Furthermore, the two metabolites [LysoPC(16:0), LysoPC(20:4)] shown to discriminate these diseases are potentially useful when combined with other, previously identified protein or metabolic biomarkers for predictive, preventive and personalized medical approach.
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Affiliation(s)
- Jun Hwa Lee
- Biomarker Branch, Research Institute, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Seung Eun Yu
- Biomarker Branch, Research Institute, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Kyung-Hee Kim
- Biomarker Branch, Research Institute, National Cancer Center, Goyang, 10408 Republic of Korea
- Omics Core Laboratory, Research Institute, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Myung Hyun Yu
- Biomarker Branch, Research Institute, National Cancer Center, Goyang, 10408 Republic of Korea
| | - In-Hye Jeong
- Biomarker Branch, Research Institute, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Jae Youl Cho
- Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419 Republic of Korea
| | - Sang-Jae Park
- Center for Liver Cancer, Hospital, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Woo Jin Lee
- Center for Liver Cancer, Hospital, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Sung-Sik Han
- Center for Liver Cancer, Hospital, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Tae Hyun Kim
- Center for Liver Cancer, Hospital, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Eun Kyung Hong
- Center for Liver Cancer, Hospital, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Sang Myung Woo
- Biomarker Branch, Research Institute, National Cancer Center, Goyang, 10408 Republic of Korea
- Center for Liver Cancer, Hospital, National Cancer Center, Goyang, 10408 Republic of Korea
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408 Republic of Korea
| | - Byong Chul Yoo
- Biomarker Branch, Research Institute, National Cancer Center, Goyang, 10408 Republic of Korea
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408 Republic of Korea
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11
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Perets R, Greenberg O, Shentzer T, Semenisty V, Epelbaum R, Bick T, Sarji S, Ben-Izhak O, Sabo E, Hershkovitz D. Mutant KRAS Circulating Tumor DNA Is an Accurate Tool for Pancreatic Cancer Monitoring. Oncologist 2018; 23:566-572. [PMID: 29371474 DOI: 10.1634/theoncologist.2017-0467] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 12/07/2017] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Many new pancreatic cancer treatment combinations have been discovered in recent years, yet the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains grim. The advent of new treatments highlights the need for better monitoring tools for treatment response, to allow a timely switch between different therapeutic regimens. Circulating tumor DNA (ctDNA) is a tool for cancer detection and characterization with growing clinical use. However, currently, ctDNA is not used for monitoring treatment response. The high prevalence of KRAS hotspot mutations in PDAC suggests that mutant KRAS can be an efficient ctDNA marker for PDAC monitoring. SUBJECTS, MATERIALS, AND METHODS Seventeen metastatic PDAC patients were recruited and serial plasma samples were collected. CtDNA was extracted from the plasma, and KRAS mutation analysis was performed using next-generation sequencing and correlated with serum CA19-9 levels, imaging, and survival. RESULTS Plasma KRAS mutations were detected in 5/17 (29.4%) patients. KRAS ctDNA detection was associated with shorter survival (8 vs. 37.5 months). Our results show that, in ctDNA positive patients, ctDNA is at least comparable to CA19-9 as a marker for monitoring treatment response. Furthermore, the rate of ctDNA change was inversely correlated with survival. CONCLUSION Our results confirm that mutant KRAS ctDNA detection in metastatic PDAC patients is a poor prognostic marker. Additionally, we were able to show that mutant KRAS ctDNA analysis can be used to monitor treatment response in PDAC patients and that ctDNA dynamics is associated with survival. We suggest that ctDNA analysis in metastatic PDAC patients is a readily available tool for disease monitoring. IMPLICATIONS FOR PRACTICE Avoiding futile chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) patients by monitoring response to treatment is of utmost importance. A novel biomarker for monitoring treatment response in PDAC, using mutant KRAS circulating tumor DNA (ctDNA), is proposed. Results, although limited by small sample numbers, suggest that ctDNA can be an effective marker for disease monitoring and that ctDNA level over time is a better predictor of survival than the dynamics of the commonly used biomarker CA19-9. Therefore, ctDNA analysis can be a useful tool for monitoring PDAC treatment response. These results should be further validated in larger sample numbers.
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Affiliation(s)
- Ruth Perets
- Departments of Oncology
- Technion-Israel Institute of Technology, Haifa, Israel
| | - Orli Greenberg
- Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | | | | | - Ron Epelbaum
- Departments of Oncology
- Technion-Israel Institute of Technology, Haifa, Israel
| | - Tova Bick
- Pathology, Rambam Health Care Campus, Haifa, Israel
| | - Shada Sarji
- Pathology, Rambam Health Care Campus, Haifa, Israel
| | - Ofer Ben-Izhak
- Pathology, Rambam Health Care Campus, Haifa, Israel
- Technion-Israel Institute of Technology, Haifa, Israel
| | - Edmond Sabo
- Pathology, Rambam Health Care Campus, Haifa, Israel
- Technion-Israel Institute of Technology, Haifa, Israel
| | - Dov Hershkovitz
- Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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12
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Hidalgo M, Álvarez R, Gallego J, Guillén-Ponce C, Laquente B, Macarulla T, Muñoz A, Salgado M, Vera R, Adeva J, Alés I, Arévalo S, Blázquez J, Calsina A, Carmona A, de Madaria E, Díaz R, Díez L, Fernández T, de Paredes BG, Gallardo ME, González I, Hernando O, Jiménez P, López A, López C, López-Ríos F, Martín E, Martínez J, Martínez A, Montans J, Pazo R, Plaza JC, Peiró I, Reina JJ, Sanjuanbenito A, Yaya R, Carrato A. Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic cancer in Spain. Clin Transl Oncol 2017; 19:667-681. [PMID: 27995549 PMCID: PMC5427095 DOI: 10.1007/s12094-016-1594-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 11/24/2016] [Indexed: 12/12/2022]
Abstract
The management of patients with pancreatic cancer has advanced over the last few years. We convey a multidisciplinary group of experts in an attempt to stablish practical guidelines for the diagnoses, staging and management of these patients. This paper summarizes the main conclusions of the working group. Patients with suspected pancreatic ductal adenocarcinoma should be rapidly evaluated and referred to high-volume centers. Multidisciplinary supervision is critical for proper diagnoses, staging and to frame a treatment plan. Surgical resection together with chemotherapy offers the highest chance for cure in early stage disease. Patients with advanced disease should be classified in treatment groups to guide systemic treatment. New chemotherapeutic regimens have resulted in improved survival. Symptomatic management is critical in this disease. Enrollment in a clinical trial is, in general, recommended.
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Affiliation(s)
- M Hidalgo
- Spanish National Cancer Centre, C/Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
- Beth Israel Deaconess Medical Center, Boston, USA.
| | - R Álvarez
- Department of Medical Oncology, Centro Integral Oncológico Clara Campal, Madrid, Spain
| | - J Gallego
- University Hospital of Elche, Elche, Spain
| | - C Guillén-Ponce
- Hospital Universitario Ramón y Cajal, Ctra. de Colmenar Viejo km. 9,100, 28034, Madrid, Spain
| | - B Laquente
- Institut Català d´Oncologia, Duran y Reynals Hospital, Hospitalet Llobregat, Barcelona, Spain
| | - T Macarulla
- Vall d'Hebrón University Hospital, Barcelona, Spain
| | - A Muñoz
- University Hospital Gregorio Marañón, Madrid, Spain
| | - M Salgado
- University Hospital of Ourense, Ourense, Spain
| | - R Vera
- Complejo Hospitalario de Navarra, Pamplona, Spain
| | - J Adeva
- University Hospital 12 de Octubre, Madrid, Spain
| | - I Alés
- Hospital Carlos Haya, Málaga, Spain
| | - S Arévalo
- University Hospital Donostia, San Sebastián, Spain
| | - J Blázquez
- Department of Radiology, University Hospital Ramón y Cajal, Madrid, Spain
- MD Anderson Hospital, Madrid, Spain
| | - A Calsina
- Department of Palliative Care, Hospital Germans Trias I Pujol, Institut Catalá d´Oncologia, Badalona, Spain
| | - A Carmona
- Department of Medical Oncology and Hematology, University Hospital Morales Messeguer, Murcia, Spain
| | - E de Madaria
- Department of Gastroenterology, Hospital General Universitario de Alicante, Alicante, Spain
| | - R Díaz
- Department of Medical Oncology, Hospital Universitari I Politècnic La Fe, Valencia, Spain
| | - L Díez
- Department of Surgery, Hospital Clínico San Carlos, Madrid, Spain
| | - T Fernández
- Department of Medical Oncology, Hospital Son Llàtzer, Palma de Mallorca, Spain
| | | | - M E Gallardo
- Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
| | - I González
- Complejo Hospitalario de Granada, Granada, Spain
| | - O Hernando
- Department of Radiotherapy, University Hospital HM Sanchinarro, Madrid, Spain
- University Hospital HM Puerta del Sur, Madrid, Spain
| | - P Jiménez
- Department of Medical Oncology, Hospital Universitario Central de Asturias, Asturias, Spain
| | - A López
- Hospital Universitario de Burgos, Burgos, Spain
| | - C López
- Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - F López-Ríos
- Department of Pathology, University Hospital HM Sanchinarro, Madrid, Spain
| | - E Martín
- Department of Surgery, Hospital Universitario de la Princesa, Madrid, Spain
| | - J Martínez
- Department of Medical Oncology, University Hospital Virgen de las Nieves, Granada, Spain
| | | | - J Montans
- Department of Pathology, Centro Anatomopatológico, Madrid, Spain
| | - R Pazo
- Department of Medical Oncology, University Hospital Miguel Servet, Saragossa, Spain
| | - J C Plaza
- Department of Pathology, University Hospital HM Sanchinarro, Madrid, Spain
| | - I Peiró
- Department of Endocrinology, Instituto Catalán de Oncología, Hospital Duran I Reynals, Hospitalet de Llobregat, Barcelona, Spain
| | - J J Reina
- Department of Medical Oncology, University Hospital Virgen de la Macarena, Seville, Spain
| | - A Sanjuanbenito
- Department of Surgery, University Hospital Ramón y Cajal, Madrid, Spain
| | - R Yaya
- Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
| | - Alfredo Carrato
- Hospital Universitario Ramón y Cajal, Ctra. de Colmenar Viejo km. 9,100, 28034, Madrid, Spain.
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13
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Kojima M, Sudo H, Kawauchi J, Takizawa S, Kondou S, Nobumasa H, Ochiai A. MicroRNA markers for the diagnosis of pancreatic and biliary-tract cancers. PLoS One 2015; 10:e0118220. [PMID: 25706130 PMCID: PMC4338196 DOI: 10.1371/journal.pone.0118220] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 01/11/2015] [Indexed: 12/21/2022] Open
Abstract
It is difficult to detect pancreatic cancer or biliary-tract cancer at an early stage using current diagnostic technology. Utilizing microRNA (miRNA) markers that are stably present in peripheral blood, we aimed to identify pancreatic and biliary-tract cancers in patients. With "3D-Gene", a highly sensitive microarray, we examined comprehensive miRNA expression profiles in 571 serum samples obtained from healthy patients, patients with pancreatic, biliary-tract, or other digestive cancers, and patients with non-malignant abnormalities in the pancreas or biliary tract. The samples were randomly divided into training and test cohorts, and candidate miRNA markers were independently evaluated. We found 81 miRNAs for pancreatic cancer and 66 miRNAs for biliary-tract cancer that showed statistically different expression compared with healthy controls. Among those markers, 55 miRNAs were common in both the pancreatic and biliary-tract cancer samples. The previously reported miR-125a-3p was one of the common markers; however, it was also expressed in other types of digestive-tract cancers, suggesting that it is not specific to cancer types. In order to discriminate the pancreato-biliary cancers from all other clinical conditions including the healthy controls, non-malignant abnormalities, and other types of cancers, we developed a diagnostic index using expression profiles of the 10 most significant miRNAs. A combination of eight miRNAs (miR-6075, miR-4294, miR-6880-5p, miR-6799-5p, miR-125a-3p, miR-4530, miR-6836-3p, and miR-4476) achieved a sensitivity, specificity, accuracy and AUC of 80.3%, 97.6%, 91.6% and 0.953, respectively. In contrast, CA19-9 and CEA gave sensitivities of 65.6% and 40.0%, specificities of 92.9% and 88.6%, and accuracies of 82.1% and 71.8%, respectively, in the same test cohort. This diagnostic index identified 18/21 operable pancreatic cancers and 38/48 operable biliary-tract cancers in the entire cohort. Our results suggest that the assessment of these miRNA markers is clinically valuable to identify patients with pancreato-biliary cancers who could benefit from surgical intervention.
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Affiliation(s)
- Motohiro Kojima
- Department of Pathology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
- * E-mail:
| | - Hiroko Sudo
- New Frontiers Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan
| | - Junpei Kawauchi
- New Frontiers Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan
| | - Satoko Takizawa
- New Frontiers Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan
| | - Satoshi Kondou
- New Projects Development Division, Toray Industries, Inc., Kamakura, Kanagawa, Japan
| | - Hitoshi Nobumasa
- New Projects Development Division, Toray Industries, Inc., Kamakura, Kanagawa, Japan
| | - Atsushi Ochiai
- Department of Pathology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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14
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Jin XL, Xu B, Wu YL. Detection of pancreatic cancer with normal carbohydrate antigen 19-9 using protein chip technology. World J Gastroenterol 2014; 20:14958-14964. [PMID: 25356057 PMCID: PMC4209560 DOI: 10.3748/wjg.v20.i40.14958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 04/14/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a method to differentiate pancreatic cancer patients from healthy or benign individuals when carbohydrate antigen (CA) 19-9 is normal.
METHODS: Forty-one serum samples from patients with pancreatic lesions and blood samples from 20 healthy individuals were collected at the first stage of the experiment according to the enrolment criteria. General characteristics and some clinical features were carefully compared to ensure that the results were reasonable. All the blood samples were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) combined with CM10 chips and a related bioinformatics analysis program to generate diagnostic models with different proteins. Forty-seven consecutive samples were tested at the next stage to verify the veracity and efficiency of the models.
RESULTS: The sex, age, and serum CA19-9 levels among the three groups (malignant, benign, and healthy) were statistically matched (P values were 0.957, 0.145, and 0.382, respectively). Two patterns were generated. Pattern 1 with four proteins theoretically had a specificity and sensitivity of 100% in distinguishing pancreatic cancer from healthy individuals, while it was 86.7% and 86.4%, respectively, in the subsequent practical verification. The positive predictive value (PPV) of the model was 86.4%. One of the four proteins was expressed highly in pancreatic cancer while the other three were expressed weakly. Pattern 2 consisted of six proteins that showed a specificity of 70.0% and sensitivity of 77.3% for differentiating malignancy from benign tumors. Its PPV reached 85.0%. Only one of these six proteins showed high expression in the malignant group.
CONCLUSION: SELDI-TOF-MS may facilitate diagnosis or differential diagnosis of pancreatic cancer when CA19-9 is normal. Pattern 1 may serve as a useful screening tool.
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