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Bai J, Xiao R, Jiang D, Luo X, Tang Y, Cui M, You L, Zhao Y. Sialic Acids: Sweet modulators fueling cancer cells and domesticating the tumor microenvironment. Cancer Lett 2025; 626:217773. [PMID: 40339953 DOI: 10.1016/j.canlet.2025.217773] [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: 03/10/2025] [Revised: 04/23/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
Tumor microenvironment (TME) can shift towards either immune activation or immunosuppression, influenced by various factors. Recent studies have underscored the pivotal role of sialic acids, a group of monosaccharides with a 9-carbon backbone, in modulating the TME. Aberrant expression or abnormal addition of sialic acids to the surface of cancer cells and within the tumor stroma has been identified as a key contributor to tumor progression. Abnormal sialylation on cancer cell surfaces can inhibit apoptosis, enhance cell proliferation, and facilitate metastasis. Notably, recent findings suggest that dysregulated sialic acid expression in the TME actively contributes to shaping an immunosuppressive niche by reducing the population of anti-tumor immune cells and impairing immune cell function. The mechanisms by which sialic acids foster immune escape and shape the immunosuppressive TME have been partially unraveled, particularly through interactions with sialic acid receptors on immune cells. Importantly, several sialic acid-targeted therapies are currently advancing into clinical trials, offering promising prospects for clinical translation. This dysregulated sialylation represents a significant opportunity for molecular diagnostics and therapeutic interventions in oncology. Targeting aberrant sialylation or disrupting the interaction between sialic acids and their receptors offers potential strategies to reprogram the TME towards an anti-tumor phenotype, thereby facilitating the advancement of innovative cancer therapies.
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Affiliation(s)
- Jialu Bai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Ruiling Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Decheng Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xiyuan Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Yuemeng Tang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Ming Cui
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Wang D, Li P, Su W, Hou L, Han J, Zhang Y, Liu L, Mu D, Xia L, Qiu L. From interference to insight: pseudo-lipidemia led to the diagnosis of Waldenström macroglobulinemia. BMC Cardiovasc Disord 2025; 25:170. [PMID: 40065247 PMCID: PMC11892186 DOI: 10.1186/s12872-025-04588-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Waldenström macroglobulinemia (WM) is a rare hematological disorder with an annual incidence of about 3 per million. Its clinical manifestations are diverse and non - specific, and approximately 30% of patients are asymptomatic, making early diagnosis challenging. This paper reports a 73-year-old female who was admitted to the hospital due to atrial fibrillation. During a physical examination several years before the hospitalization, an elevated CA19-9 was detected, but the cause remained unclear after multiple outpatient visits. During cardiac markers testing, an abnormal serum index (HIL) suggested a lipidemic sample, yet the sample appeared clear visually. A Sia water test showed positive result, and subsequent serum protein electrophoresis confirmed the presence of M protein, leading to the diagnosis of WM. During the treatment in the following 6 years, it was found that the levels of CA19-9 and IgM fluctuated in parallel. Abnormal lipid indices and albumin-globulin ratio can provide important clues for the diagnosis of WM, but they may be overlooked in clinical practice. When the total protein increases with normal or decreased albumin levels, a reflex test of serum protein electrophoresis can help with early diagnosis. This case shows that understanding and using interference information in laboratory tests can assist in the diagnosis of WM.
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Affiliation(s)
- Danchen Wang
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
| | - Pengchang Li
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
| | - Wei Su
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
| | - Li'an Hou
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
| | - Jianhua Han
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
| | - Ying Zhang
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
| | - Li Liu
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
| | - Danni Mu
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
| | - Liangyu Xia
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China.
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
| | - Ling Qiu
- Department of Laboratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No. 1 Shuaifu Yuan, Dongcheng District, Beijing, 100730, China
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Li H, Sun W, Fu S, Wang J, Jin B, Zhang S, Liu Y, Zhang Q, Wang H. Prognostic value of the preoperative prognostic nutritional and systemic immunoinflammatory indexes in patients with colorectal cancer. BMC Cancer 2025; 25:403. [PMID: 40045249 PMCID: PMC11884152 DOI: 10.1186/s12885-025-13828-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 02/27/2025] [Indexed: 03/09/2025] Open
Abstract
INTRODUCTION Colorectal cancer (CRC) is a common malignant tumor of the digestive tract. Although many prognostic indicators are currently available, it remains unclear which indicators are the most beneficial for patients with CRC. Therefore, there is a critical need to identify a simple, convenient and accurate prognostic indicator. PURPOSE To investigate the clinical significance of the systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) as prognostic indicators for the survival of patients with CRC. METHODS The clinical data of CRC patients admitted to the general surgery ward of Taizhou People's Hospital affiliated to Nanjing Medical University from January 2015 to January 2018 were retrospectively analyzed. Two prognostic indicators (SII and PNI) were compared to evaluate their prognostic value in CRC patients. RESULTS Based on these variables, we constructed a LASSO prediction model. The AUC (Area Under the Curve) value and 95% CI of the training group were 0.917 (0.858-0.976) compared to 0.932 (0.846-1.000) in the validation group. We found that CEA > 5 ng/mL, tumor stage, pathological type, postoperative complications, and PNI were associated with the five-year survival rate of CRC patients. Receiver Operating Characteristic Curves (ROC) were drawn to assess the prediction accuracy of the model. The AUC and 95% CI of the training group were 0.913 (0.854-0.972), while the AUC and 95% CI of the validation group were 0.954 (0.899-1.000). CONCLUSIONS PNI is an independent risk factor for postoperative complications associated with CRC and a powerful tool for predicting survival outcomes in CRC patients.
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Affiliation(s)
- Haifeng Li
- Department of General Surgery, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, 366 Taihu Road, Taizhou, China
- Postgraduate School, Dalian Medical University, Dalian, China
| | - Wei Sun
- Hefei High-Tech Cardiovascular Hospital, Hefei, China
| | - Shengfeng Fu
- Department of Hepatobiliary Surgery, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, Taizhou, China
| | - Junfeng Wang
- Department of General Surgery, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, 366 Taihu Road, Taizhou, China
- Postgraduate School, Dalian Medical University, Dalian, China
| | - Bin Jin
- Department of General Surgery, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, 366 Taihu Road, Taizhou, China
- Postgraduate School, Dalian Medical University, Dalian, China
| | - Shuo Zhang
- Department of General Surgery, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, 366 Taihu Road, Taizhou, China
- Postgraduate School, Dalian Medical University, Dalian, China
| | - Yujun Liu
- Department of General Surgery, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, 366 Taihu Road, Taizhou, China
- Taizhou Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Qinyang Zhang
- Department of Orthopedics, The First Affliated Hospital of Chongqing Medical University, Chongqing, China.
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, China.
| | - Honggang Wang
- Department of General Surgery, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Nanjing Medical University, 366 Taihu Road, Taizhou, China.
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Codrich M, Biasotto A, D’Aurizio F. Circulating Biomarkers of Thyroid Cancer: An Appraisal. J Clin Med 2025; 14:1582. [PMID: 40095491 PMCID: PMC11900207 DOI: 10.3390/jcm14051582] [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: 01/13/2025] [Revised: 02/16/2025] [Accepted: 02/23/2025] [Indexed: 03/19/2025] Open
Abstract
Thyroid cancer is the most prevalent endocrine cancer. The prognosis depends on the type and stage at diagnosis. Thyroid cancer treatments involve surgery, possibly followed by additional therapeutic options such as hormone therapy, radiation therapy, targeted therapy and chemotherapy. Besides the well-known thyroid tumor biomarkers, new circulating biomarkers are now emerging. Advances in genomic, transcriptomic and proteomic technologies have allowed the development of novel tumor biomarkers. This review explores the current literature data to critically analyze the benefits and limitations of routinely measured circulating biomarkers for the diagnosis and monitoring of thyroid cancer. The review also sheds light on new circulating biomarkers, focusing on the challenges of their use in the clinical management of thyroid cancer, underlining the need for the identification of a new generation of circulating biomarkers.
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Affiliation(s)
- Marta Codrich
- Department of Medicine (DMED), University of Udine, 33100 Udine, Italy; (M.C.); (A.B.)
| | - Alessia Biasotto
- Department of Medicine (DMED), University of Udine, 33100 Udine, Italy; (M.C.); (A.B.)
- Institute of Clinical Pathology, Academic Hospital “Santa Maria della Misericordia”, Azienda Sanitaria Universitaria Friuli Centrale, 33100 Udine, Italy
| | - Federica D’Aurizio
- Department of Medicine (DMED), University of Udine, 33100 Udine, Italy; (M.C.); (A.B.)
- Institute of Clinical Pathology, Academic Hospital “Santa Maria della Misericordia”, Azienda Sanitaria Universitaria Friuli Centrale, 33100 Udine, Italy
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Athanasiou A, Kureshi N, Wittig A, Sterner M, Huber R, Palma NA, King T, Schiess R. Biomarker Discovery for Early Detection of Pancreatic Ductal Adenocarcinoma (PDAC) Using Multiplex Proteomics Technology. J Proteome Res 2025; 24:315-322. [PMID: 39699878 PMCID: PMC11705213 DOI: 10.1021/acs.jproteome.4c00752] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/27/2024] [Accepted: 12/13/2024] [Indexed: 12/20/2024]
Abstract
Early detection of pancreatic ductal adenocarcinoma (PDAC) can improve survival but is hampered by the absence of early disease symptoms. Imaging remains key for surveillance but is cumbersome and may lack sensitivity to detect small tumors. CA19-9, the only FDA-approved blood biomarker for PDAC, is insufficiently sensitive and specific to be recommended for surveillance. We aimed to discover a blood-based protein signature to improve PDAC detection in our main target population consisting of stage I or II PDAC patients (n = 75) and various controls including healthy controls (n = 50), individuals at high risk (genetic and familial) for PDAC (n = 47), or those under surveillance for an intraductal papillary mucinous neoplasm (n = 36). Roughly 3000 proteins were measured using Olink multiplex technology and conventional immunoassays. Machine learning combined biomarker candidates into 4- to 6-plex signatures. These signatures significantly (p < 0.001) outperformed CA19-9 with 84% sensitivity at 95% specificity, compared to CA19-9's sensitivity of 53% in the target population. Exploratory analysis was performed in new-onset diabetes (n = 81) and chronic pancreatitis (n = 50) patients. In conclusion, 41 promising biomarker candidates across multiple signatures were identified using proteomics technology and will be further tested in an independent cohort.
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Affiliation(s)
| | - Natasha Kureshi
- Immunovia
Inc., 26 Forest Street,
Suite 110, Marlborough, Massachusetts 01752, United States
| | - Anja Wittig
- Proteomedix
AG, Wagistrasse 23, CH-8952 Schlieren, Switzerland
| | - Maria Sterner
- Immunovia
AB, Medicon Village,
Scheelevägen 8, SE-223 63 Lund, Sweden
| | - Ramy Huber
- Proteomedix
AG, Wagistrasse 23, CH-8952 Schlieren, Switzerland
| | - Norma A. Palma
- Immunovia
Inc., 26 Forest Street,
Suite 110, Marlborough, Massachusetts 01752, United States
| | - Thomas King
- Immunovia
Inc., 26 Forest Street,
Suite 110, Marlborough, Massachusetts 01752, United States
| | - Ralph Schiess
- Proteomedix
AG, Wagistrasse 23, CH-8952 Schlieren, Switzerland
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Wang J, Xu K, Zhou C, Wang X, Zuo J, Zeng C, Zhou P, Gao X, Zhang L, Wang X. A novel model based on clinical and computed tomography (CT) indices to predict the risk factors of postoperative major complications in patients undergoing pancreaticoduodenectomy. PeerJ 2024; 12:e18753. [PMID: 39713149 PMCID: PMC11663404 DOI: 10.7717/peerj.18753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 12/03/2024] [Indexed: 12/24/2024] Open
Abstract
Background Postoperative complications are prone to occur in patients after radical pancreaticoduodenectomy (PD). This study aimed to construct and validate a model for predicting postoperative major complications in patients after PD. Methods The clinical data of 360 patients who underwent PD were retrospectively collected from two centers between January 2019 and December 2023. Visceral adipose volume (VAV) and subcutaneous adipose volume (SAV) were measured using three-dimensional (3D) computed tomography (CT) reconstruction. According to the Clavien-Dindo classification system, the postoperative complications were graded. Subsequently, a predictive model was constructed based on the results of least absolute shrinkage and selection operator (LASSO) multivariate logistic regression analysis and stepwise (stepAIC) selection. The nomogram was internally validated by the training and test cohort. The discriminatory ability and clinical utility of the nomogram were evaluated by area under the receiver operating characteristic (ROC) curve (AUC), calibration curve, and decision curve analysis (DCA). Results The major complications occurred in 13.3% (n = 48) of patients after PD. The nomogram revealed that high VAV/SAV, high system inflammation response index (SIRI), high triglyceride glucose-body mass index (TyG-BMI), low prognostic nutritional index (PNI) and CA199 ≥ 37 were independent risk factors for major complications. The C-index of this model was 0.854 (95%CI [0.800-0.907]), showing excellent discrimination. The calibration curve demonstrated satisfactory concordance between nomogram predictions and actual observations. The DCA curve indicated the substantial clinical utility of the nomogram. Conclusion The model based on clinical and CT indices demonstrates good predictive performance and clinical benefit for major complications in patients undergoing PD.
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Affiliation(s)
- Jiaqi Wang
- Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Kangjing Xu
- Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Changsheng Zhou
- Department of Radiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xinbo Wang
- Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Junbo Zuo
- Department of General Surgery, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
| | - Chenghao Zeng
- Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Pinwen Zhou
- Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xuejin Gao
- Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Li Zhang
- Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xinying Wang
- Department of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
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Bockorny B, Muthuswamy L, Huang L, Hadisurya M, Maria Lim C, Tsai LL, Gill RR, Wei JL, Bullock AJ, Grossman JE, Besaw RJ, Narasimhan S, Tao WA, Perea S, Sawhney MS, Freedman SD, Hildago M, Iliuk A, Muthuswamy SK. A large-scale proteomics resource of circulating extracellular vesicles for biomarker discovery in pancreatic cancer. eLife 2024; 12:RP87369. [PMID: 39693144 DOI: 10.7554/elife.87369] [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] [Indexed: 12/19/2024] Open
Abstract
Pancreatic cancer has the worst prognosis of all common tumors. Earlier cancer diagnosis could increase survival rates and better assessment of metastatic disease could improve patient care. As such, there is an urgent need to develop biomarkers to diagnose this deadly malignancy. Analyzing circulating extracellular vesicles (cEVs) using 'liquid biopsies' offers an attractive approach to diagnose and monitor disease status. However, it is important to differentiate EV-associated proteins enriched in patients with pancreatic ductal adenocarcinoma (PDAC) from those with benign pancreatic diseases such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN). To meet this need, we combined the novel EVtrap method for highly efficient isolation of EVs from plasma and conducted proteomics analysis of samples from 124 individuals, including patients with PDAC, benign pancreatic diseases and controls. On average, 912 EV proteins were identified per 100 µL of plasma. EVs containing high levels of PDCD6IP, SERPINA12, and RUVBL2 were associated with PDAC compared to the benign diseases in both discovery and validation cohorts. EVs with PSMB4, RUVBL2, and ANKAR were associated with metastasis, and those with CRP, RALB, and CD55 correlated with poor clinical prognosis. Finally, we validated a seven EV protein PDAC signature against a background of benign pancreatic diseases that yielded an 89% prediction accuracy for the diagnosis of PDAC. To our knowledge, our study represents the largest proteomics profiling of circulating EVs ever conducted in pancreatic cancer and provides a valuable open-source atlas to the scientific community with a comprehensive catalogue of novel cEVs that may assist in the development of biomarkers and improve the outcomes of patients with PDAC.
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Affiliation(s)
- Bruno Bockorny
- Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, United States
- Harvard Medical School, Boston, United States
| | | | - Ling Huang
- Henry Ford Cancer Institute, Detroit, United States
| | - Marco Hadisurya
- Department of Biochemistry, Purdue University West Lafayette, West Lafayette, United States
| | | | - Leo L Tsai
- Harvard Medical School, Boston, United States
- Department of Radiology, Beth Israel Deaconess Medical Center, Boston, United States
| | - Ritu R Gill
- Harvard Medical School, Boston, United States
- Department of Radiology, Beth Israel Deaconess Medical Center, Boston, United States
| | - Jesse L Wei
- Harvard Medical School, Boston, United States
- Department of Radiology, Beth Israel Deaconess Medical Center, Boston, United States
| | - Andrea J Bullock
- Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, United States
- Harvard Medical School, Boston, United States
| | | | - Robert J Besaw
- Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, United States
| | | | - Weiguo Andy Tao
- Department of Biochemistry, Purdue University West Lafayette, West Lafayette, United States
| | - Sofia Perea
- Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, United States
| | - Mandeep S Sawhney
- Harvard Medical School, Boston, United States
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, United States
| | - Steven D Freedman
- Harvard Medical School, Boston, United States
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, United States
| | - Manuel Hildago
- Division of Hematology-Oncology, Weill Cornell Medical College, New York, United States
- New York-Presbyterian Hospital, New York, United States
| | - Anton Iliuk
- Tymora Analytical Operations, West Lafayette, United States
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Wang X, Liu L, Liu ZP, Wang JY, Dai HS, Ou X, Zhang CC, Yu T, Liu XC, Pang SJ, Fan HN, Bai J, Jiang Y, Zhang YQ, Wang ZR, Chen ZY, Li AG. Machine learning model to predict early recurrence in patients with perihilar cholangiocarcinoma planned treatment with curative resection: a multicenter study. J Gastrointest Surg 2024; 28:2039-2047. [PMID: 39368645 DOI: 10.1016/j.gassur.2024.09.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 09/11/2024] [Accepted: 09/28/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Early recurrence is the leading cause of death for patients with perihilar cholangiocarcinoma (pCCA) after surgery. Identifying high-risk patients preoperatively is important. This study aimed to construct a preoperative prediction model for the early recurrence of patients with pCCA to facilitate planned treatment with curative resection. METHODS This study ultimately enrolled 400 patients with pCCA after curative resection in 5 hospitals between 2013 and 2019. They were randomly divided into training (n = 300) and testing groups (n = 100) at a ratio of 3:1. Associated variables were identified via least absolute shrinkage and selection operator (LASSO) regression. Four machine learning models were constructed: support vector machine, random forest (RF), logistic regression, and K-nearest neighbors. The predictive ability of the models was evaluated via receiving operating characteristic (ROC) curves, precision-recall curve (PRC) curves, and decision curve analysis. Kaplan-Meier (K-M) survival curves were drawn for the high-/low-risk population. RESULTS Five factors: carbohydrate antigen 19-9, tumor size, total bilirubin, hepatic artery invasion, and portal vein invasion, were selected by LASSO regression. In both the training and testing groups, the ROC curve (area under the curve: 0.983 vs 0.952) and the PRC (0.981 vs 0.939) showed that RF was the best. The cutoff value for distinguishing high- and low-risk patients was 0.51. K-M survival curves revealed that in both groups, there was a significant difference in RFS between high- and low-risk patients (P < .001). CONCLUSION This study used preoperative variables from a large, multicenter database to construct a machine learning model that could effectively predict the early recurrence of pCCA in patients to facilitate planned treatment with curative resection and help clinicians make better treatment decisions.
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Affiliation(s)
- Xiang Wang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Li Liu
- Department of Digital Medicine, School of Biomedical Engineering and Medical Imaging, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhi-Peng Liu
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Hepato-pancreato-biliary Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jiao-Yang Wang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Hai-Su Dai
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xia Ou
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Cheng-Cheng Zhang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ting Yu
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xing-Chao Liu
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, Chengdu, China
| | - Shu-Jie Pang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Hai-Ning Fan
- Department of Hepatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, China
| | - Jie Bai
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yan Jiang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yan-Qi Zhang
- Department of Health Statistics, College of Military Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zi-Ran Wang
- Department of General Surgery, 903rd Hospital of People's Liberation Army, Hangzhou, China
| | - Zhi-Yu Chen
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ai-Guo Li
- Department of General Surgery, Youyang Hospital, A Branch of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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9
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Goggins M. The role of biomarkers in the early detection of pancreatic cancer. Fam Cancer 2024; 23:309-322. [PMID: 38662265 PMCID: PMC11309746 DOI: 10.1007/s10689-024-00381-4] [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: 03/09/2024] [Accepted: 03/19/2024] [Indexed: 04/26/2024]
Abstract
Pancreatic surveillance can detect early-stage pancreatic cancer and achieve long-term survival, but currently involves annual endoscopic ultrasound and MRI/MRCP, and is recommended only for individuals who meet familial/genetic risk criteria. To improve upon current approaches to pancreatic cancer early detection and to expand access, more accurate, inexpensive, and safe biomarkers are needed, but finding them has remained elusive. Newer approaches to early detection, such as using gene tests to personalize biomarker interpretation, and the increasing application of artificial intelligence approaches to integrate complex biomarker data, offer promise that clinically useful biomarkers for early pancreatic cancer detection are on the horizon.
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Affiliation(s)
- Michael Goggins
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD, 21231, USA.
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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10
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Ando Y, Dbouk M, Yoshida T, Saba H, Abou Diwan E, Yoshida K, Dbouk A, Blackford AL, Lin MT, Lennon AM, Burkhart RA, He J, Sokoll L, Eshleman JR, Canto MI, Goggins M. Using Tumor Marker Gene Variants to Improve the Diagnostic Accuracy of DUPAN-2 and Carbohydrate Antigen 19-9 for Pancreatic Cancer. J Clin Oncol 2024; 42:2196-2206. [PMID: 38457748 PMCID: PMC11191066 DOI: 10.1200/jco.23.01573] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 10/25/2023] [Accepted: 12/22/2023] [Indexed: 03/10/2024] Open
Abstract
PURPOSE Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance. MATERIALS AND METHODS Using a training/validation study design, FUT2/FUT3 genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay. RESULTS In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] v 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUCPR) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2. CONCLUSION Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.
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Affiliation(s)
- Yohei Ando
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Mohamad Dbouk
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Takeichi Yoshida
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Helena Saba
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Elizabeth Abou Diwan
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Kanako Yoshida
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Ali Dbouk
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Amanda L. Blackford
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Ming-Tseh Lin
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Anne Marie Lennon
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Richard A. Burkhart
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Jin He
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Lori Sokoll
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - James R. Eshleman
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Marcia Irene Canto
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
| | - Michael Goggins
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD
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11
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Said SA, Perlmutter BC, Wehrle CJ, Chang J, Hossain MS, Naffouje S, Joyce D, Simon R, Walsh RM, Augustin T. Tumor Size Combined With CA-19 Level Improves Prediction of Survival of Patients With Pancreatic Adenocarcinoma Undergoing Perioperative Chemotherapy and Resection. Am Surg 2024; 90:1397-1405. [PMID: 38513242 DOI: 10.1177/00031348241241738] [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] [Indexed: 03/23/2024]
Abstract
BACKGROUND AND OBJECTIVE Five-year survival in pancreatic adenocarcinoma is less than 20%. While previous studies have postulated that a carbohydrate antigen 19-9 (CA19-9) threshold could predict outcome of resection, the role for CA19-9 in decision-making remains unclear. This study aims to assess whether CA19-9 levels combined with tumor size improve prediction of post-resection survival. METHOD A retrospective analysis was conducted on 109 patients with pancreatic adenocarcinoma who underwent perioperative chemotherapy followed by resection. The primary outcome of mortality was, divided into short (<1 year) or prolonged (>2 years). Univariate and multivariable analyses compared the tumor size-adjusted CA19-9 between the outcome groups. RESULTS Twenty-seven (24.78%) and eighty-two (75.23%) patients were in the short survival and prolonged-survival groups, respectively. The mean CA19-9 was significantly greater in the short vs prolonged group (P < .001). Analyzing CA19-9 level by tumor size, the association of high CA19-9 and short survival was significant for small (≤2 cm) and large tumor (>4 cm), but not for intermediate-size tumors (2-4 cm). Adjusting for preoperative variable did not change this association. CONCLUSION CA 19-9 in combination with tumor size better identifies patients with prolonged post-resection survival. This prediction is most accurate in patients with either small (≤2 cms) or large (>4 cms) tumors compared to intermediate-size tumors.
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Affiliation(s)
- Sayf A Said
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | | | - Chase J Wehrle
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Jenny Chang
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | | | - Samer Naffouje
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Daniel Joyce
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Robert Simon
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - R Matthew Walsh
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Toms Augustin
- Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
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12
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Wen YR, Lin XW, Zhou YW, Xu L, Zhang JL, Chen CY, He J. N-glycan biosignatures as a potential diagnostic biomarker for early-stage pancreatic cancer. World J Gastrointest Oncol 2024; 16:659-669. [PMID: 38577461 PMCID: PMC10989390 DOI: 10.4251/wjgo.v16.i3.659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/21/2023] [Accepted: 01/18/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of less than 10%, owing to its late-stage diagnosis. Early detection of pancreatic cancer (PC) can significantly increase survival rates. AIM To identify the serum biomarker signatures associated with early-stage PDAC by serum N-glycan analysis. METHODS An extensive patient cohort was used to determine a biomarker signature, including patients with PDAC that was well-defined at an early stage (stages I and II). The biomarker signature was derived from a case-control study using a case-cohort design consisting of 29 patients with stage I, 22 with stage II, 4 with stage III, 16 with stage IV PDAC, and 88 controls. We used multiparametric analysis to identify early-stage PDAC N-glycan signatures and developed an N-glycan signature-based diagnosis model called the "Glyco-model". RESULTS The biomarker signature was created to discriminate samples derived from patients with PC from those of controls, with a receiver operating characteristic area under the curve of 0.86. In addition, the biomarker signature combined with cancer antigen 19-9 could discriminate patients with PDAC from controls, with a receiver operating characteristic area under the curve of 0.919. Glyco-model demonstrated favorable diagnostic performance in all stages of PC. The diagnostic sensitivity for stage I PDAC was 89.66%. CONCLUSION In a prospective validation study, this serum biomarker signature may offer a viable method for detecting early-stage PDAC.
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Affiliation(s)
- Yan-Rong Wen
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Xia-Wen Lin
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Yu-Wen Zhou
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing 210008, Jiangsu Province, China
| | - Lei Xu
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing 210008, Jiangsu Province, China
| | - Jun-Li Zhang
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing 210008, Jiangsu Province, China
| | - Cui-Ying Chen
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing 210008, Jiangsu Province, China
| | - Jian He
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
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13
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Dbouk M, Abe T, Koi C, Ando Y, Saba H, Abou Diwan E, MacGregor-Das A, Blackford AL, Mocci E, Beierl K, Dbouk A, He J, Burkhart R, Lennon AM, Sokoll L, Canto MI, Eshleman JR, Goggins M. Diagnostic Performance of a Tumor Marker Gene Test to Personalize Serum CA19-9 Reference Ranges. Clin Cancer Res 2023; 29:4178-4185. [PMID: 37566230 PMCID: PMC10570677 DOI: 10.1158/1078-0432.ccr-23-0655] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/25/2023] [Accepted: 08/08/2023] [Indexed: 08/12/2023]
Abstract
PURPOSE CA19-9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and evaluated its diagnostic performance for pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN A representative set of controls from the Cancer of the Pancreas Screening study was identified for each FUT functional group. Diagnostic sensitivity was determined first in a testing set of 234 PDAC cases, followed by a 134-case validation set, all of whom had undergone resection with curative intent without neoadjuvant therapy. Tumor marker gene testing was performed in the Johns Hopkins Molecular Diagnostics Laboratory. CA19-9 levels were measured in the Hopkins Clinical Chemistry lab. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative ability of CA19-9 alone versus with the gene test. RESULTS Applying the CA19-9 standard cutoff (<36 U/mL) to all 716 subjects yielded a 68.8% sensitivity in the test set of cases, 67.2% in the validation set, at 91.4% specificity. Applying 99th percentile cutoffs according to each individual's FUT group (3, 34.9, 41.8, and 89.2, for the FUT3-null, FUT-low, FUT-intermediate, and FUT-high groups, respectively) yielded a diagnostic sensitivity for CA19-9 in the first set of cases of 66.7%, 65.7% in the validation set, at 98.9% specificity. ROC analysis for CA19-9 alone yielded an AUC of 0.84; with the tumor marker gene test, AUC improved to 0.92 (P < 0.001). CONCLUSIONS Using a tumor marker gene test to personalize an individual's CA19-9 reference range significantly improves diagnostic accuracy.
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Affiliation(s)
- Mohamad Dbouk
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Toshiya Abe
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Chiho Koi
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Yohei Ando
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Helena Saba
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Elizabeth Abou Diwan
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Anne MacGregor-Das
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Amanda L. Blackford
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Evelina Mocci
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Katie Beierl
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Ali Dbouk
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Jin He
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Richard Burkhart
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Anne Marie Lennon
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Lori Sokoll
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Marcia Irene Canto
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - James R. Eshleman
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Michael Goggins
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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14
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Lee JH, Kim DK, Lee MY, Lim HS, Kwon MJ, Lee YT, Yoon KJ, Park CH. The Association of Carbohydrate Antigen (CA) 19-9 Levels and Low Skeletal Muscle Mass in Healthy Adults. Nutrients 2023; 15:3394. [PMID: 37571330 PMCID: PMC10421491 DOI: 10.3390/nu15153394] [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: 06/19/2023] [Revised: 07/21/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
Carbohydrate antigen 19-9 (CA 19-9) is a commonly used tumor marker for pancreatic cancer. However, CA 19-9 can be overexpressed in several benign inflammatory diseases. We investigated the relationship between high CA 19-9 level and low muscle mass (LMM) in healthy adults without cancer. Participants who underwent evaluation of muscle mass and CA 19-9 were included. Exclusion criteria were any malignancy, cardiovascular disease, tuberculosis, and chronic lung/liver disease. Participants were classified into "normal", "mild LMM", and "severe LMM" groups based on the skeletal muscle mass index. Multivariable logistic regression analyses were conducted to assess the association of high CA 19-9 with muscle mass status. A total of 263,061 adults were included. The mean age and SMI were 41.03 years and 7.13 kg/m2. After adjustments for various confounders, high CA 19-9 was independently associated with mild LMM (adjusted odds ratio, 1.677 [95% confidence interval, 1.533-1.834]) and severe LMM (2.651 [2.126-3.306]) compared to the normal group. Furthermore, the association between high CA 19-9 and severe LMM was stronger in men than in women. Elevated CA 19-9 levels were independently associated with a higher prevalence of LMM in healthy adults without cancer. Therefore, increased CA 19-9 could be utilized as a novel biomarker for sarcopenia.
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Affiliation(s)
- Jae Hyun Lee
- Department of Rehabilitation Medicine, Kosin University College of Medicine, Busan 49267, Republic of Korea;
- Department of Artificial Intelligence Convergence, Pukyong National University, Busan 48513, Republic of Korea
| | - Dong-Kun Kim
- Department of Physical and Rehabilitation Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Republic of Korea; (D.-K.K.); (H.-S.L.); (Y.-T.L.); (K.J.Y.)
| | - Mi-Yeon Lee
- Division of Biostatistics, Department of R&D Management, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea;
| | - Han-Sol Lim
- Department of Physical and Rehabilitation Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Republic of Korea; (D.-K.K.); (H.-S.L.); (Y.-T.L.); (K.J.Y.)
| | - Min-Jung Kwon
- Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea;
| | - Yong-Taek Lee
- Department of Physical and Rehabilitation Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Republic of Korea; (D.-K.K.); (H.-S.L.); (Y.-T.L.); (K.J.Y.)
| | - Kyung Jae Yoon
- Department of Physical and Rehabilitation Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Republic of Korea; (D.-K.K.); (H.-S.L.); (Y.-T.L.); (K.J.Y.)
| | - Chul-Hyun Park
- Department of Physical and Rehabilitation Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Republic of Korea; (D.-K.K.); (H.-S.L.); (Y.-T.L.); (K.J.Y.)
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15
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Masterson AN, Chowdhury NN, Fang Y, Yip-Schneider MT, Hati S, Gupta P, Cao S, Wu H, Schmidt CM, Fishel ML, Sardar R. Amplification-Free, High-Throughput Nanoplasmonic Quantification of Circulating MicroRNAs in Unprocessed Plasma Microsamples for Earlier Pancreatic Cancer Detection. ACS Sens 2023; 8:1085-1100. [PMID: 36853001 DOI: 10.1021/acssensors.2c02105] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that is often detected at an advanced stage. Earlier diagnosis of PDAC is key to reducing mortality. Circulating biomarkers such as microRNAs are gaining interest, but existing technologies require large sample volumes, amplification steps, extensive biofluid processing, lack sensitivity, and are low-throughput. Here, we present an advanced nanoplasmonic sensor for the highly sensitive, amplification-free detection and quantification of microRNAs (microRNA-10b, microRNA-let7a) from unprocessed plasma microsamples. The sensor construct utilizes uniquely designed -ssDNA receptors attached to gold triangular nanoprisms, which display unique localized surface plasmon resonance (LSPR) properties, in a multiwell plate format. The formation of -ssDNA/microRNA duplex controls the nanostructure-biomolecule interfacial electronic interactions to promote the charge transfer/exciton delocalization processes and enhance the LSPR responses to achieve attomolar (10-18 M) limit of detection (LOD) in human plasma. This improve LOD allows the fabrication of a high-throughput assay in a 384-well plate format. The performance of nanoplasmonic sensors for microRNA detection was further assessed by comparing with the qRT-PCR assay of 15 PDAC patient plasma samples that shows a positive correlation between these two assays with the Pearson correlation coefficient value >0.86. Evaluation of >170 clinical samples reveals that oncogenic microRNA-10b and tumor suppressor microRNA-let7a levels can individually differentiate PDAC from chronic pancreatitis and normal controls with >94% sensitivity and >94% specificity at a 95% confidence interval (CI). Furthermore, combining both oncogenic and tumor suppressor microRNA levels significantly improves differentiation of PDAC stages I and II versus III and IV with >91% and 87% sensitivity and specificity, respectively, in comparison to the sensitivity and specificity values for individual microRNAs. Moreover, we show that the level of microRNAs varies substantially in pre- and post-surgery PDAC patients (n = 75). Taken together, this ultrasensitive nanoplasmonic sensor with excellent sensitivity and specificity is capable of assaying multiple biomarkers simultaneously and may facilitate early detection of PDAC to improve patient care.
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Affiliation(s)
- Adrianna N Masterson
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, Indiana 46202, United States
| | - Nayela N Chowdhury
- Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
| | - Yue Fang
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Michele T Yip-Schneider
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Sumon Hati
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, Indiana 46202, United States
| | - Prashant Gupta
- Department of Mechanical Engineering, Washington University, St. Louis, Missouri 63130, United States
| | - Sha Cao
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Huangbing Wu
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - C Max Schmidt
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Melissa L Fishel
- Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Rajesh Sardar
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, Indiana 46202, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
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16
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Lindgaard SC, Sztupinszki Z, Maag E, Hansen CP, Chen IM, Johansen AZ, Hasselby JP, Bojesen SE, Nielsen D, Johansen JS. Prognostic value of circulating proteins in patients undergoing surgery for pancreatic cancer. Cancer Med 2023; 12:3972-3986. [PMID: 36250429 PMCID: PMC9972037 DOI: 10.1002/cam4.5240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/26/2022] [Accepted: 09/01/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Less than 20% of patients are diagnosed with resectable disease. Identifying truly resectable disease is challenging because 20%-40% of the patients subjected to resection are found to have advanced disease during surgery. The aim of our study was to identify panels of circulating proteins that could be used to distinguish patients with unresectable PDAC from patients with resectable PDAC and to identify prognostic signatures for both groups. METHODS We measured 92 circulating immuno-oncology-related proteins using the proximity extension assay from Olink Proteomics in 273 patients eligible for surgery for PDAC. Two bioinformaticians worked independently of one another on the same data. LASSO and Ridge regression were used in the statistical analyses. RESULTS One protein index for determining resectability had an AUC value of 0.66. Several indices for prognosis had AUC values between 0.50 and 0.75 and were therefore not better than existing prognostic markers. DISCUSSION Our study did not reveal any new high-performing protein panels that could be used to identify patients with inoperable PDAC before surgery. The panel of 92 proteins investigated has previously been found to be applicable for diagnostic use in patients with PDAC, but it does not seem to warrant further investigation regarding resectability in the subgroup of patients with PDAC referred to surgery.
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Affiliation(s)
- Sidsel C. Lindgaard
- Department of OncologyCopenhagen University Hospital–Herlev and GentofteHerlevDenmark
| | | | | | - Carsten P. Hansen
- Department of SurgeryCopenhagen University Hospital – RigshospitaletCopenhagenDenmark
| | - Inna M. Chen
- Department of OncologyCopenhagen University Hospital–Herlev and GentofteHerlevDenmark
| | - Astrid Z. Johansen
- Department of OncologyCopenhagen University Hospital–Herlev and GentofteHerlevDenmark
| | - Jane P. Hasselby
- Department of PathologyCopenhagen University Hospital – RigshospitaletCopenhagenDenmark
| | - Stig E. Bojesen
- Department of Clinical BiochemistryCopenhagen University Hospital ‐ Herlev and GentofteHerlevDenmark
- Institute of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Dorte Nielsen
- Department of OncologyCopenhagen University Hospital–Herlev and GentofteHerlevDenmark
- Institute of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Julia S. Johansen
- Department of OncologyCopenhagen University Hospital–Herlev and GentofteHerlevDenmark
- Institute of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Department of MedicineCopenhagen University Hospital ‐ Herlev and GentofteHerlevDenmark
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17
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Desai S, Guddati AK. Carcinoembryonic Antigen, Carbohydrate Antigen 19-9, Cancer Antigen 125, Prostate-Specific Antigen and Other Cancer Markers: A Primer on Commonly Used Cancer Markers. World J Oncol 2023; 14:4-14. [PMID: 36895994 PMCID: PMC9990734 DOI: 10.14740/wjon1425] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 11/28/2022] [Indexed: 03/01/2023] Open
Abstract
Cancer markers are molecules produced by cancer cells which may serve to identify the presence of cancer. Cancer markers can be differentiated as serum-based, radiology-based and tissue-based, and are one of the most important tools in diagnosing, staging and monitoring of treatment of many cancers. The most used cancer markers are serum cancer markers due to its relative ease and lower cost of testing. However, serum cancer markers have poor mass screening utilization due to poor positive predictive value. Several markers such as prostate-specific antigen (PSA), beta-human chorionic gonadotropin (B-hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) are used to aid in diagnosis of cancer in cases of high suspicion. Serum markers such as carcinoembryonic antigen (CEA), AFP, carbohydrate antigen 19-9 (CA 19-9), and 5-hydroxyindoleacetic acid (5-HIAA) play a significant role in assessing disease prognosis as well as response to treatment. This work reviews the role of some of the biomarkers in the diagnosis and treatment of cancer.
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Affiliation(s)
- Shreya Desai
- Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
| | - Achuta K Guddati
- Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
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18
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Zhang J, Zhang Y, Guo Y. Combination of clinical and MRI features in diagnosing ovarian granulosa cell tumor: A comparison with other ovarian sex cord-gonadal stromal tumors. Eur J Radiol 2023; 158:110593. [PMID: 36434968 DOI: 10.1016/j.ejrad.2022.110593] [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: 06/29/2022] [Revised: 10/09/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022]
Abstract
PURPOSE To evaluate the combination of magnetic resonance imaging (MRI) findings and clinical features in diagnosing ovarian granulosa cell tumor (OGCT) and comparing OGCTs with other ovarian sex cord-gonadal stromal tumors (OSGTs). METHODS Women who underwent MRI and were surgically confirmed with OSGTs between January 2015 and January 2022 were included in the study. Histology was used as a primary method of diagnosis. T1WI, T2WI, and DWI MR scans were performed for all patients. All MR images were reviewed by two radiologists. The clinic baseline characteristics of all patients were recorded. RESULTS A total of 58 patients were enrolled, with 21 OGCTs found in 20 patients and 39 other OSGTs found in 38 patients. In terms of clinical, the proportion of vaginal discharge/bleeding and menstrual abnormalities were significantly higher in OGCTs than in the control group. A multivariate analysis of the combined clinical MRI revealed that symptomatic, T2 signals of the solid component, Honeycomb-sign, Swiss cheese-sign, and ADC values were independent features for discriminating between OGCTs and other OSGTs. Clinical features, MRI features, and a combined model were established; the areas under the curve of the three models in predicting OGCTs and other OSGTs were 0.694, 0.852, and 0.927, respectively. The DeLong test showed that the combined model had the highest efficiency in predicting OGCTs (p < 0.05), which was significantly different from the AUC of the other two models (p < 0.05). CONCLUSIONS Combining clinic and MRI findings helps differentiate OGCTs from other OSGTs. These results help optimize clinical management and indicate that radiologists should focus on clinical information to help improve diagnostic accuracy.
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Affiliation(s)
- Jing Zhang
- Dept Imaging Ctr, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Dept Imaging Ctr, Northwest Women's and Children's Hospital, Xi'an, Shaanxi 710061, China
| | - Yi Zhang
- Dept Imaging Ctr, Northwest Women's and Children's Hospital, Xi'an, Shaanxi 710061, China
| | - Youmin Guo
- Dept Imaging Ctr, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
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19
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Borrebaeck CA, Mellby LD, King TC. Biomarkers for the Early Detection of Pancreatic Ductal Adenocarcinoma. GASTROINTESTINAL CANCERS 2022:85-100. [PMID: 36343153 DOI: 10.36255/exon-publications-gastrointestinal-cancers-biomarkers-pancreatic-cancer] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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20
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Marciel MP, Haldar B, Hwang J, Bhalerao N, Bellis SL. Role of tumor cell sialylation in pancreatic cancer progression. Adv Cancer Res 2022; 157:123-155. [PMID: 36725107 PMCID: PMC11342334 DOI: 10.1016/bs.acr.2022.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is currently the third leading cause of cancer death. The aggressiveness of PDAC stems from late diagnosis, early metastasis, and poor efficacy of current chemotherapies. Thus, there is an urgent need for effective biomarkers for early detection of PDAC and development of new therapeutic strategies. It has long been known that cellular glycosylation is dysregulated in pancreatic cancer cells, however, tumor-associated glycans and their cognate glycosylating enzymes have received insufficient attention as potential clinical targets. Aberrant glycosylation affects a broad range of pathways that underpin tumor initiation, metastatic progression, and resistance to cancer treatment. One of the prevalent alterations in the cancer glycome is an enrichment in a select group of sialylated glycans including sialylated, branched N-glycans, sialyl Lewis antigens, and sialylated forms of truncated O-glycans such as the sialyl Tn antigen. These modifications affect the activity of numerous cell surface receptors, which collectively impart malignant characteristics typified by enhanced cell proliferation, migration, invasion and apoptosis-resistance. Additionally, sialic acids on tumor cells engage inhibitory Siglec receptors on immune cells to dampen anti-tumor immunity, further promoting cancer progression. The goal of this review is to summarize the predominant changes in sialylation occurring in pancreatic cancer, the biological functions of sialylated glycoproteins in cancer pathogenesis, and the emerging strategies for targeting sialoglycans and Siglec receptors in cancer therapeutics.
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Affiliation(s)
- Michael P Marciel
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Barnita Haldar
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jihye Hwang
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Nikita Bhalerao
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Susan L Bellis
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States.
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21
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Coppola A, La Vaccara V, Farolfi T, Fiore M, Cammarata R, Ramella S, Coppola R, Caputo D. Role of CA 19.9 in the Management of Resectable Pancreatic Cancer: State of the Art and Future Perspectives. Biomedicines 2022; 10:2091. [PMID: 36140192 PMCID: PMC9495897 DOI: 10.3390/biomedicines10092091] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/14/2022] [Accepted: 08/23/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Surgery still represents the gold standard of treatment for resectable pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant treatments (NAT), currently proposed for borderline and locally advanced PDACs, are gaining momentum even in resectable tumors due to the recent interesting concept of "biological resectability". In this scenario, CA 19.9 is having increasing importance in preoperative staging and in the choice of therapeutic strategies. We aimed to assess the state of the art and to highlight the future perspectives of CA 19.9 use in the management of patients with resectable pancreatic cancer. METHODS A PubMed database search of articles published up to December 2021 has been carried out. RESULTS Elevated pre-operative levels of CA 19.9 have been associated with reduced overall survival, nodal involvement, and margin status positivity after surgery. These abilities of CA 19.9 increase when combined with radiological or different biological criteria. Unfortunately, due to strong limitations of previously published articles, CA 19.9 alone cannot be yet considered as a key player in resectable pancreatic cancer patient management. CONCLUSION The potential of CA 19.9 must be fully explored in order to standardize its role in the "biological staging" of patients with resectable pancreatic cancer.
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Affiliation(s)
- Alessandro Coppola
- General Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Vincenzo La Vaccara
- General Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
| | - Tommaso Farolfi
- General Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Michele Fiore
- Radiation Oncology, Campus Bio-Medico University, 00128 Rome, Italy
| | - Roberto Cammarata
- General Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Sara Ramella
- Radiation Oncology, Campus Bio-Medico University, 00128 Rome, Italy
| | - Roberto Coppola
- General Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- General Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Damiano Caputo
- General Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- General Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
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22
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Sena P, Mancini S, Pedroni M, Reggiani Bonetti L, Carnevale G, Roncucci L. Expression of Autophagic and Inflammatory Markers in Normal Mucosa of Individuals with Colorectal Adenomas: A Cross Sectional Study among Italian Outpatients Undergoing Colonoscopy. Int J Mol Sci 2022; 23:5211. [PMID: 35563601 PMCID: PMC9104783 DOI: 10.3390/ijms23095211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/04/2023] Open
Abstract
Colorectal cancer (CRC) ranks among the three most common cancers in terms of both cancer incidence and cancer-related deaths in Western industrialized countries. Lifetime risk of colorectal cancer may reach 6% of the population living in developed countries. In the current era of personalized medicine, CRC is no longer considered as a single entity. In more recent years many studies have described the distinct differences in epidemiology, pathogenesis, genetic and epigenetic alterations, molecular pathways and outcome depending on the anatomical site. The aim of our study is to assess in a multidimensional model the association between metabolic status and inflammatory and autophagic changes in the normal colorectal mucosa classified as right-sided, left-sided and rectum, and the presence of adenomas. One hundred and sixteen patients undergoing colonoscopy were recruited and underwent a complete serum lipid profile, immunofluorescence analysis of colonic biopsies for MAPLC3 and myeloperoxidase expression, matched with clinical and anthropometric characteristics. Presence of adenomas correlated with cholesterol (total and LDL) levels, IL-6 levels, and MAPLC3 tissue expression, especially in the right colon. In conclusion, serum IL-6 amount and autophagic markers could be good predictors of the presence of colorectal adenomas.
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Affiliation(s)
- Paola Sena
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy;
| | - Stefano Mancini
- Department of Internal Medicine and Rehabilitation, Santa Maria Bianca Hospital, Mirandola 6, 41037 Modena, Italy;
| | - Monica Pedroni
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy; (M.P.); (L.R.B.); (L.R.)
| | - Luca Reggiani Bonetti
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy; (M.P.); (L.R.B.); (L.R.)
| | - Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy;
| | - Luca Roncucci
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy; (M.P.); (L.R.B.); (L.R.)
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23
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Gunn AH, Tashie C, Wolf S, Troy JD, Zafar Y. Tumor marker response to SARS-CoV-2 infection among patients with cancer. Cancer Med 2022; 11:2865-2872. [PMID: 35289488 PMCID: PMC9110907 DOI: 10.1002/cam4.4646] [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: 10/26/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 11/10/2022] Open
Abstract
Background Inflammatory responses from benign conditions can cause non‐cancer‐related elevations in tumor markers. The severe acute respiratory coronavirus 2 (SARS‐CoV‐2) induces a distinct viral inflammatory response, resulting in coronavirus disease 2019 (COVID‐19). Clinical data suggest carcinoembryonic antigen (CEA), carbohydrate antigen 19–9 (CA 19–9), and cancer antigen 125 (CA 125) levels might rise in patients with COVID‐19. However, available data excludes cancer patients, so little is known about the effect of COVID‐19 on tumor markers among cancer patients. Methods We conducted a case series and identified patients with a positive SARS‐CoV‐2 PCR test, diagnosis of a solid tumor malignancy, and a CEA, CA 19–9, CA 125, or CA 27–29 laboratory test. Cancer patients with documented COVID‐19 infection and at least one pre‐ and two post‐infection tumor marker measurements were included. We abstracted the electronic health record for demographics, cancer diagnosis, treatment, evidence of cancer progression, date and severity of COVID‐19 infection, and tumor marker values. Results Seven patients were identified with a temporary elevation of tumor marker values during the post‐COVID‐19 period. Elevation in tumor marker occurred within 56 days of COVID‐19 infection for all patients. Tumor markers subsequently decreased at the second time point in the post‐infectious period among all patients. Conclusion We report temporary elevations of cancer tumor markers in the period surrounding COVID‐19 infection. To our knowledge this is the first report of this phenomenon in cancer patients and has implications for clinical management and future research.
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Affiliation(s)
| | | | - Steven Wolf
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA
| | - Jesse D Troy
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA
| | - Yousuf Zafar
- Duke University School of Medicine, Durham, North Carolina, USA.,Duke Cancer Institute, Durham, North Carolina, USA
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24
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Haga Y, Ueda K. Glycosylation in cancer: its application as a biomarker and recent advances of analytical techniques. Glycoconj J 2022; 39:303-313. [DOI: 10.1007/s10719-022-10043-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/07/2022] [Accepted: 01/18/2022] [Indexed: 11/24/2022]
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Brand RE, Persson J, Bratlie SO, Chung DC, Katona BW, Carrato A, Castillo M, Earl J, Kokkola A, Lucas AL, Moser AJ, DeCicco C, Mellby LD, King TC. Detection of Early-Stage Pancreatic Ductal Adenocarcinoma From Blood Samples: Results of a Multiplex Biomarker Signature Validation Study. Clin Transl Gastroenterol 2022; 13:e00468. [PMID: 35166713 PMCID: PMC8963856 DOI: 10.14309/ctg.0000000000000468] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 02/08/2022] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION The IMMray PanCan-d test combines an 8-plex biomarker signature with CA19-9 in a proprietary algorithm to detect pancreatic ductal adenocarcinoma (PDAC) in serum samples. This study aimed to validate the clinical performance of the IMMray PanCan-d test and to better understand test performance in Lewis-null (le/le) individuals who cannot express CA19-9. METHODS Serum samples from 586 individuals were analyzed with the IMMray PanCan-d biomarker signature and CA19-9 assay, including 167 PDAC samples, 203 individuals at high risk of familial/hereditary PDAC, and 216 healthy controls. Samples were collected at 11 sites in the United States and Europe. The study was performed by Immunovia, Inc (Marlborough, MA), and sample identity was blinded throughout the study. Test results were automatically generated using validated custom software with a locked algorithm and predefined decision value cutoffs for sample classification. RESULTS The IMMray PanCan-d test distinguished PDAC stages I and II (n = 56) vs high-risk individuals with 98% specificity and 85% sensitivity and distinguished PDAC stages I-IV vs high-risk individuals with 98% specificity and 87% sensitivity. We identified samples with a CA19-9 value of 2.5 U/mL or less as probable Lewis-null (le/le) individuals. Excluding these 55 samples from the analysis increased the IMMray PanCan-d test sensitivity to 92% for PDAC stages I-IV (n = 157) vs controls (n = 379) while maintaining specificity at 99%; test sensitivity for PDAC stages I and II increased from 85% to 89%. DISCUSSION These results demonstrate the IMMray PanCan-d blood test can detect PDAC with high specificity (99%) and sensitivity (92%).
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Affiliation(s)
- Randall E. Brand
- Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Jan Persson
- Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden;
| | - Svein Olav Bratlie
- Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden;
| | - Daniel C. Chung
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA;
| | - Bryson W. Katona
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA;
| | - Alfredo Carrato
- Molecular Epidemiology and Predictive Markers in Cancer Group, Ramon y Cajal University Hospital, Alcala University, IRYCIS, CIBERONC, Madrid, Spain, Pancreatic Cancer Europe Chairperson, Brussels, Belgium
| | - Marién Castillo
- Molecular Epidemiology and Predictive Markers in Cancer Group, Ramón y Cajal University Hospital, IRYCIS, CIBERONC, Madrid, Spain;
| | - Julie Earl
- Molecular Epidemiology and Predictive Markers in Cancer Group, Ramón y Cajal University Hospital, IRYCIS, CIBERONC, Madrid, Spain;
| | - Arto Kokkola
- Helsinki University Hospital, Helsinki, Finland;
| | - Aimee L. Lucas
- Division of Gastroenterology, Mt. Sinai Medical Center, New York, New York, USA;
| | - A. James Moser
- Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
| | - Corinne DeCicco
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
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The imprecision for a high-sensitivity cardiac troponin assay and a CA 19-9 assay in samples with high C-reactive protein concentrations. Clin Chim Acta 2022; 524:192-193. [PMID: 34808114 DOI: 10.1016/j.cca.2021.11.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 11/21/2022]
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Qiu H, Liu C, Huang M, Shen S, Wang W. Prognostic Value of Combined CA19-9 with Aspartate Aminotransferase to Lymphocyte Ratio in Patients with Intrahepatic Cholangiocarcinoma After Hepatectomy. Cancer Manag Res 2021; 13:5969-5980. [PMID: 34377017 PMCID: PMC8349206 DOI: 10.2147/cmar.s320380] [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: 05/15/2021] [Accepted: 07/16/2021] [Indexed: 02/05/2023] Open
Abstract
Purpose The prognosis of intrahepatic cholangiocarcinoma (ICC) patients after surgical resection remains poor. Effective prognostic biomarkers are expected to stratify ICC patients and optimize their treatment strategies. To investigate the prognostic value of carbohydrate antigen 19-9 (CA19-9), aspartate aminotransferase to lymphocyte ratio index (ALRI), and their combination (CAC) in predicting long-term outcomes in ICC patients after hepatectomy. Patients and Methods ICC patients underwent initial hepatectomy for curative purpose from January 2009 to September 2017 were reviewed retrospectively. Area under the receiver operating characteristics curve (AUC) was used to distinguish the identification effectiveness of three different measures. Kaplan–Meier curves and Cox proportional hazards regression were used to assess the value of preoperative CAC grade in predicting overall survival (OS) and disease-free survival (DFS). Results A total of 530 patients were included and randomly divided into two groups (derivation cohort and validation cohort). During a median follow-up of 18 months (1–115.4 months), 317 patients (59.8%) died and 381 patients (71.9%) developed tumor recurrence. Lower ALRI, decreased serum CA19-9 level and CAC grade were found to be associated with better OS and DFS (both P<0.001). Importantly, the AUC for CAC grade was significantly greater than ALRI and CA19-9. In addition, results from Cox proportional hazards regression from both cohorts suggest that tumor number, node invasion, and CAC grade as independent prognostic factors for both OS and DFS. Conclusion This study demonstrated that CAC grade is a valuable biomarker for the prognosis of ICC patients. Specifically, patients with elevated CAC grades were correlated to worse long-term outcome after the hepatectomy. Our data suggest that increased CAC grades can be used to stratify patients and help to decide their treatment strategies.
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Affiliation(s)
- Haizhou Qiu
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Chang Liu
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Min Huang
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Shu Shen
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
| | - Wentao Wang
- Department of Liver Surgery and Liver Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China
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Ge X, Tang L, Wang Y, Wang N, Zhou J, Deng X, Zhong Y, Li Q, Wang F, Jiang G, Miao L. The diagnostic value of exosomal miRNAs in human bile of malignant biliary obstructions. Dig Liver Dis 2021; 53:760-765. [PMID: 33257140 DOI: 10.1016/j.dld.2020.11.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Diagnosis of malignant biliary obstruction is complicated and lacks accuracy. Exosomes may be secreted by malignant tumors; intact miRNAs from exosomes might serve as potential biomarkers for the disease. AIM To identify exosomal microRNAs in human bile among benign and malignant biliary obstructions. METHODS Bile samples were collected from patients undergoing therapeutic endoscopic retrograde cholangiopancreatography for biliary obstruction. Exosome microRNAs were determined by RNA-sequencing in the discovery cohort, which comprising benign (n = 5) cases and malignant biliary obstruction (n = 5) cases. Then, the diagnostic performance of the two up-regulated microRNAs (mir-483-5p and mir-126-3p) of bile exosomes was verified by analysis of 82 patients with a diagnosis of malignant (n=37) or nonmalignant (n=45) biliary obstruction. RESULTS In both cohorts, the expressions of mir-483-5p and mir-126-3p were significantly higher in bile exosomes samples from patients with malignant biliary obstructions than controls. In the verification cohort, the two miRNAs can distinguished the benign and malignant groups with high diagnostic accuracy and specificity; the diagnostic values of the two microRNAs were better than serum carbohydrate antigen 19-9 (CA19-9), area under the curve (AUC) were 0.81 and 0.74. CONCLUSION The expression of exosomal mir-483-5p and mir-126-3p in the bile samples discriminates between patients with malignant and nonmalignant biliary obstructions. CLINICAL TRIAL REGISTRATION NO NCT03102268.
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Affiliation(s)
- Xianxiu Ge
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lingyu Tang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Youli Wang
- Department of Clinical Laboratory, Nanjing First Hospital, Nanjing, China
| | - Ni Wang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Zhou
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xueting Deng
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuan Zhong
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Quanpeng Li
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fei Wang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guobin Jiang
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lin Miao
- Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Lindgaard SC, Sztupinszki Z, Maag E, Chen IM, Johansen AZ, Jensen BV, Bojesen SE, Nielsen DL, Hansen CP, Hasselby JP, Nielsen KR, Szallasi Z, Johansen JS. Circulating Protein Biomarkers for Use in Pancreatic Ductal Adenocarcinoma Identification. Clin Cancer Res 2021; 27:2592-2603. [PMID: 33737308 DOI: 10.1158/1078-0432.ccr-20-4215] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/07/2021] [Accepted: 03/03/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Most patients are diagnosed at an advanced stage where curative surgery is not an option. The aim of this study was to identify a panel of circulating proteins that could distinguish patients with PDAC from non-PDAC individuals. EXPERIMENTAL DESIGN We investigated 92 proteins known to be involved in inflammation, development, and progression of PDAC using the Olink immuno-oncology panel in serum samples from 701 patients with PDAC (stage I-IV), 102 patients with nonmalignant pancreatic diseases, and 180 healthy blood donors. Patients were included prospectively between 2008 and 2018. Plasma carbohydrate antigen 19-9 (CA19-9) was measured in all samples. The protein panels with the best diagnostic performances were developed by two bioinformaticians working independently, using LASSO and Ridge regression models. RESULTS Two panels of proteins (index I, containing 9 proteins + CA19-9, and index II, containing 23 proteins + CA19-9) were identified. Index I was able to discriminate patients with PDAC from all patients with non-PDAC, with a ROC AUC value of 0.92 [95% confidence interval (CI), 0.89-0.96] in the discovery cohort and 0.92 (95% CI, 0.87-0.97) in the replication cohort. For index II, the AUC value was 0.96 (95% CI, 0.95-0.98) in the discovery cohort and 0.93 (95% CI, 0.90-0.96) in the replication cohort. All nine serum proteins of index I were found in index II. CONCLUSIONS This study identified two circulating protein indices with the potential to discriminate between individuals with and without PDAC.
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Affiliation(s)
- Sidsel C Lindgaard
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
| | | | | | - Inna M Chen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Astrid Z Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Benny V Jensen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Stig E Bojesen
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Dorte L Nielsen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten P Hansen
- Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jane P Hasselby
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Kaspar R Nielsen
- Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
| | - Zoltan Szallasi
- Danish Cancer Society Research Center, Copenhagen, Denmark
- Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Julia S Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
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30
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McLellan P, Henriques J, Ksontini F, Doat S, Hammel P, Desrame J, Trouilloud I, Louvet C, Pietrasz D, Vernerey D, Bachet JB. Prognostic value of the early change in neutrophil-to-lymphocyte ratio in metastatic pancreatic adenocarcinoma. Clin Res Hepatol Gastroenterol 2021; 45:101541. [PMID: 33055007 DOI: 10.1016/j.clinre.2020.08.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 07/30/2020] [Accepted: 08/31/2020] [Indexed: 02/04/2023]
Abstract
In metastatic pancreatic adenocarcinoma, a high neutrophil-to-lymphocyte ratio (NLR) at diagnosis is a marker of poor prognosis. The prognostic role of baseline NLR and NLR change during first-line chemotherapy were determined. We conducted a retrospective study by using data from a single-center prospective cohort and a randomized open-label, multicenter, randomized trial. Two hundred and twelve patients were analyzed. Baseline NLR>5 was an independent marker of poor prognosis for overall survival (HR=2.01, 95% CI 1.33-3.05; P=0.001) and progression-free survival (PFS; HR=1.80, 95% CI 1.23-2.65; P=0.0026). According to NLR dynamics (n=172), patients with NLR≤5 on days 1 and 15 had a significantly better prognosis than those with NLR≤5 on day 1 and NLR>5 on day 15 (HR=2.23, 95% CI 1.18-4.21; P=0.013), NLR >5 on day 1 and NLR ≤5 on day 15 (HR=3.25, 95% CI 1.86-5.68; P<0.001), and NLR>5 on days 1 and 15 (HR=3.37, 95% CI 1.93-5.90; P<0.001). Over time, bad responders (PFS <6 months) had significantly higher mean NLR than good responders (PFS>6 months; group effect: P<0.0001). Seven out of eight patients with baseline NLR>5 had circulating tumor DNA. This study confirmed the independent prognostic value of baseline NLR >5 in metastatic pancreatic cancer. The change in NLR early during chemotherapy was also a prognostic indicator in patients with NLR ≤5.
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Affiliation(s)
- Paul McLellan
- Sorbonne Université, 4 Place Jussieu, 75005, Paris, France; Department of Hepato-Gastroenterology, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital 75013, APHP, Paris, France
| | - Julie Henriques
- Department of Methodology and Quality of Life Oncology, University Hospital, 3 Boulevard Alexandre Fleming, 25000 Besancon, France; Bourgogne Franche-Comté Université, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, 8 rue du Docteur Jean-François-Xavier Girod, 25020 Besançon, France
| | - Feryel Ksontini
- Department of Oncology, Institute Salah-Azaïz, Boulevard du 9 avril 1938, 1006 Tunis, Tunisia
| | - Solène Doat
- Department of Hepato-Gastroenterology, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital 75013, APHP, Paris, France
| | - Pascal Hammel
- Department of Digestive Oncology, Hôpital Beaujon, 100 Boulevard du General Leclerc, 92110 Clichy, France
| | - Jérome Desrame
- Department of Gastroenterology, Hôpital Privé Jean Mermoz, 55 avenue Jean Mermoz, 69008 Lyon, France
| | - Isabelle Trouilloud
- Department of Oncology, Hôpital Saint-Antoine, 186 rue du Faubourg Saint Antoine, 75012 Paris, France
| | - Christophe Louvet
- Department of Oncology, Institut Mutualiste Montsouris, 54 avenue Jourdan, 75014 Paris, France
| | - Daniel Pietrasz
- Department of Hepato-Pancreato-Biliary Surgery, CHB, Hôpital Paul Brousse, 12 Avenue Paul Vaillant Couturier, 94800 Villejuif, France
| | - Dewi Vernerey
- Department of Methodology and Quality of Life Oncology, University Hospital, 3 Boulevard Alexandre Fleming, 25000 Besancon, France; Bourgogne Franche-Comté Université, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, 8 rue du Docteur Jean-François-Xavier Girod, 25020 Besançon, France
| | - Jean-Baptiste Bachet
- Sorbonne Université, 4 Place Jussieu, 75005, Paris, France; Department of Hepato-Gastroenterology, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital 75013, APHP, Paris, France.
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31
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Zhang Y, Yao Y, Xu Y, Li L, Gong Y, Zhang K, Zhang M, Guan Y, Chang L, Xia X, Li L, Jia S, Zeng Q. Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients. Nat Commun 2021; 12:11. [PMID: 33397889 PMCID: PMC7782482 DOI: 10.1038/s41467-020-20162-8] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023] Open
Abstract
Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient's genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R2 = 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.
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Affiliation(s)
- Yongliang Zhang
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100089, P. R. China
| | - Yu Yao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shanxi, P. R. China
| | - Yaping Xu
- Geneplus-Beijing Institute, Beijing, 102206, P. R. China
| | - Lifeng Li
- Geneplus-Beijing Institute, Beijing, 102206, P. R. China
| | - Yan Gong
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100089, P. R. China
| | - Kai Zhang
- Department of Cancer Prevention, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100010, P. R. China
| | - Meng Zhang
- Department of Molecular Diagnostics, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China
| | - Yanfang Guan
- Geneplus-Beijing Institute, Beijing, 102206, P. R. China
| | - Lianpeng Chang
- Geneplus-Beijing Institute, Beijing, 102206, P. R. China
| | - Xuefeng Xia
- Geneplus-Beijing Institute, Beijing, 102206, P. R. China
| | - Lin Li
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, 100010, P. R. China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100010, P. R. China
| | - Shuqin Jia
- Department of Molecular Diagnostics, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, P. R. China.
| | - Qiang Zeng
- Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100089, P. R. China.
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Zhang BQ, Dai XY, Ye QY, Chang L, Wang ZW, Li XQ, Li YN. Spontaneous resolution of idiopathic intestinal obstruction after pneumonia: A case report. World J Clin Cases 2020; 8:4512-4520. [PMID: 33083412 PMCID: PMC7559674 DOI: 10.12998/wjcc.v8.i19.4512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 08/04/2020] [Accepted: 08/19/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Duodenal obstruction is a common clinical scenario that can either be mechanical or a pseudo-obstruction. Clinical management of intestinal obstruction starts from localization and proceeds to histological examination of the stenotic intestine. Systemic factors and dysfunction of distant organs might contribute to the development of intestinal obstruction. Here, we report a unique case of idiopathic mechanical duodenal obstruction, which resolved spontaneously after 3 mo of conservative treatment, but was followed by intestinal pseudo-obstruction.
CASE SUMMARY An 84-year-old woman presented with worsened postprandial vomiting accompanied by prolonged pneumonia. Thorough noninvasive investigations revealed complete circumferential stenosis in the descending duodenum without known cause. Exploratory surgery was postponed due to septic shock and possible pulmonary fungal infection. Conservative treatment for 3 mo for ileus and control of pulmonary infection resolved the intestinal obstruction completely. Unfortunately, 2 wk later, she had regurgitation and postprandial vomiting again, complicated by deteriorating wheezing and dyspnea. Computed tomography revealed a dilated stomach and proximal duodenum without new intestinal stricture or pulmonary infiltration. The patient fully recovered after combined treatment with antireflux agents, enema, prokinetics, and bronchodilators.
CONCLUSION This complicated case highlights the inter-relationship of local and systemic contributions to ileus and gut dysfunction, which requires multidisciplinary treatment.
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Affiliation(s)
- Bing-Qing Zhang
- Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Xiao-Yan Dai
- International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Qiu-Yue Ye
- International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Long Chang
- Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Zhi-Wei Wang
- Interventional Section, Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Xiao-Qing Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yong-Ning Li
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
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Balestro E, Castelli G, Bernardinello N, Cocconcelli E, Biondini D, Fracasso F, Rea F, Saetta M, Baraldo S, Spagnolo P. CA 19-9 serum levels in patients with end-stage idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs): Correlation with functional decline. Chron Respir Dis 2020; 17:1479973120958428. [PMID: 32969271 PMCID: PMC7521048 DOI: 10.1177/1479973120958428] [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] [Indexed: 01/21/2023] Open
Abstract
Idiopathic pulmonary fibrosis presents a progressive and heterogeneous functional
decline. CA 19-9 has been proposed as biomarker to predict disease course, but
its role remains unclear. We assessed CA 19-9 levels and clinical data in
end-stage ILD patients (48 IPF and 20 non-IPF ILD) evaluated for lung
transplant, to correlate these levels with functional decline. Patients were
categorized based on their rate of functional decline as slow (n = 20; ΔFVC%pred
≤ 10%/year) or rapid progressors (n = 28; ΔFVC%pred ≥ 10%/year). Nearly half of
the entire patients (n = 32; 47%) had CA 19-9 levels ≥37kU/L. CA 19-9 levels in
IPF were not different from non-IPF ILD populations, however, the latter group
had a median CA 19-9 level above the normal cut-off value of 37 KU/l (60
[17–247] kU/L). Among IPF patients, CA 19-9 was higher in slow than in rapid
progressors with a trend toward significance (33vs17kU/L; p = 0.055). In the
whole population, CA19-9 levels were inversely related with ΔFVC/year (r =
−0.261; p = 0.03), this correlation remained in IPF patients, particularly in
rapid progressors (r = −0.51; p = 0.005), but not in non. Moreover, IPF rapid
progressors with normal CA 19-9 levels showed the greater ΔFVC/year compared to
those with abnormal CA 19-9 (0.95 vs. 0.65 L/year; p = 0.03). In patients with
end-stage ILD, CA 19-9 may represent a marker of disease severity, whereas its
level is inversely correlated with functional decline, particularly among IPF
rapid progressors.
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Mas L, Schwarz L, Bachet JB. Adjuvant chemotherapy in pancreatic cancer: state of the art and future perspectives. Curr Opin Oncol 2020; 32:356-363. [PMID: 32541325 DOI: 10.1097/cco.0000000000000639] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW The modalities of management of resectable pancreatic ductal adenocarcinoma (PDAC) have evolved in recent years with new practice guidelines on adjuvant chemotherapy and results of randomized phase III trials. The aim of this review is to describe the state of the art in this setting and to highlight future possible perspectives. RECENT FINDINGS Resectable PDAC is the tumor without vascular contact or a limited venous contact without vein irregularity. Several pathologic and biologic robust prognostic factors such as an R0 resection defined by a margin at least 1 mm have been validated. In phase III trials, the doublet gemcitabine-capecitabine provided a statistically significant, albeit modest overall survival benefit, but failed to show an improvement in relapse-free survival. Similarly, gemcitabine plus nab-paclitaxel did not increase disease-free survival. Modified FOLFIRINOX led to improved disease-free survival, overall survival, and metastasis-free survival, with acceptable toxicity. In the future, prognostic and/or predictive biomarkers could lead the optimization of therapeutic strategies and neoadjuvant treatment could become a standard of care in PDAC. SUMMARY After curative intent resection, modified FOLFIRINOX is the standard of care in adjuvant in fit patients with PDAC. Others regimens (monotherapy or gemcitabine-based) are an option in unfit patients.
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Affiliation(s)
- Léo Mas
- Department of Hepato-gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris
| | - Lilian Schwarz
- Department of Digestive Surgery, Rouen University Hospital
- Department of Genomic and Personalized Medicine in Cancer and Neurological Disorders, Normandie University, UNIROUEN, UMR 1245 INSERM, Rouen University Hospital, Rouen
| | - Jean-Baptiste Bachet
- Department of Hepato-gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris
- Sorbonne University, UPMC University, Paris, France
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Complementary Use of Carbohydrate Antigens Lewis a, Lewis b, and Sialyl-Lewis a (CA19.9 Epitope) in Gastrointestinal Cancers: Biological Rationale Towards A Personalized Clinical Application. Cancers (Basel) 2020; 12:cancers12061509. [PMID: 32527016 PMCID: PMC7352550 DOI: 10.3390/cancers12061509] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/03/2020] [Accepted: 06/06/2020] [Indexed: 12/14/2022] Open
Abstract
Carbohydrate antigen 19.9 (CA19.9) is used as a tumor marker for clinical and research purposes assuming that it is abundantly produced by gastrointestinal cancer cells due to a cancer-associated aberrant glycosylation favoring its synthesis. Recent data has instead suggested a different picture, where immunodetection on tissue sections matches biochemical and molecular data. In addition to CA19.9, structurally related carbohydrate antigens Lewis a and Lewis b are, in fact, undetectable in colon cancer, due to the down-regulation of a galactosyltransferase necessary for their synthesis. In the pancreas, no differential expression of CA19.9 or cognate glycosyltransferases occurs in cancer. Ductal cells only express such Lewis antigens in a pattern affected by the relative levels of each glycosyltransferase, which are genetically and epigenetically determined. The elevation of circulating antigens seems to depend on the obstruction of neoplastic ducts and loss of polarity occurring in malignant ductal cells. Circulating Lewis a and Lewis b are indeed promising candidates for monitoring pancreatic cancer patients that are negative for CA19.9, but not for improving the low diagnostic performance of such an antigen. Insufficient biological data are available for gastric and bile duct cancer. Studying each patient in a personalized manner determining all Lewis antigens in the surgical specimens and in the blood, together with the status of the tissue-specific glycosylation machinery, promises fruitful advances in translational research and clinical practice.
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Kim S, Park BK, Seo JH, Choi J, Choi JW, Lee CK, Chung JB, Park Y, Kim DW. Carbohydrate antigen 19-9 elevation without evidence of malignant or pancreatobiliary diseases. Sci Rep 2020; 10:8820. [PMID: 32483216 PMCID: PMC7264353 DOI: 10.1038/s41598-020-65720-8] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 05/08/2020] [Indexed: 02/07/2023] Open
Abstract
Although carbohydrate antigen 19-9 (CA 19-9) may be elevated in benign diseases, elevated CA 19-9 may cause a fear of cancer and unnecessary follow-up studies. Research on how to approach systematically in this case is very limited. The purpose of this study was to analyze the clinical features and the causes of CA 19-9 elevation without evidence of malignant or pancreatobiliary diseases. We retrospectively reviewed the medical records of patients who had CA 19-9 elevation (≥80 U/mL) and were found to be unrelated to cancer after follow-up. After exclusion, 192 patients were included in this study. The median level of CA 19-9 was 136.5 U/mL. The causes of CA 19-9 elevation were determined in 147 (76.6%) patients, and that was unknown in 45 (23.4%). The estimated causative diseases were hepatic diseases in 63 patients, pulmonary diseases in 32, gynecologic diseases in 38, endocrine diseases in 13, and spleen disease in 1. Of 45 patients with unknown cause, 35 had normalization of CA 19-9 and 10 had persistently elevated CA 19-9. In conclusion, CA 19-9 elevation without malignancies or pancreatobiliary diseases should be systematically evaluated and followed up. We suggest an algorithm to investigate the causes and follow up these patients.
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Affiliation(s)
- Sunyoung Kim
- Division of Gastroenterology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Byung Kyu Park
- Division of Gastroenterology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea.
| | - Jeong Hun Seo
- Division of Gastroenterology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Jinyoung Choi
- Division of Gastroenterology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Jong Won Choi
- Division of Gastroenterology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Chun Kyon Lee
- Division of Gastroenterology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Jae Bock Chung
- Division of Gastroenterology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Yongjung Park
- Department of Laboratory Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Dong Wook Kim
- Department of Policy Research Affairs, National Health Insurance Service Ilsan Hospital, Goyang, Korea
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Sun KD, Zhang YJ, Zhu LP, Yang B, Wang SY, Yu ZH, Zhang HC, Chen X. Abnormal serum carbohydrate antigen 19-9 levels in a patient with splenic retiform haemangioendothelioma concomitant with hepatic amyloidosis: A case report. World J Clin Cases 2020; 8:1108-1115. [PMID: 32258081 PMCID: PMC7103981 DOI: 10.12998/wjcc.v8.i6.1108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/21/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Carbohydrate antigen 19-9 (CA 19-9) is a glycoprotein that is used as a reliable tool for monitoring pancreatic cancer. Serum CA 19-9 levels are increased in patients suffering from liver, lung, and other non-malignant diseases. Haemangioendothelioma is a vascular neoplasm with a borderline biological behaviour. However, no case of haemangioendothelioma has yet been reported to be associated with CA 19-9.
CASE SUMMARY A 54-year-old Chinese man was referred to our hospital for discontinuous fatigue and unintentional weight loss for over one year. Laboratory investigations revealed an elevated serum CA 19-9 concentration of 39 IU/mL (reference interval, 0–37 IU/mL) over one year before admission. Afterwards, coagulopathy appeared, and the patient’s serum CA 19-9 concentration increased continuously. At the time of admission, abdominal pain and haemorrhagic shock burst occurred, and emergency medical operation was performed. Laboratory investigations conducted upon admission showed a serum CA19-9 concentration of 392.56 IU/mL. Surgical resection of the spleen was undertaken, and pathological examination showed retiform haemangioendothelioma. The patient developed jaundice ten days after surgical excision of the spleen. Pathological examination of needle biopsy samples of the liver yielded a diagnosis of hepatic amyloidosis.
CONCLUSION We describe a rare case of splenic retiform haemangioenthelioma concomitant with hepatic amyloidosis. Physicians should note abnormal serum CA 19-9 levels with early symptoms of fatigue and unintentional weight loss.
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Affiliation(s)
- Kai-Di Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yu-Jie Zhang
- Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Lan-Ping Zhu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Bo Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Sai-Yu Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zi-Han Yu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hai-Cheng Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
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Bronkhorst AJ, Ungerer V, Holdenrieder S. Early detection of cancer using circulating tumor DNA: biological, physiological and analytical considerations. Crit Rev Clin Lab Sci 2019:1-17. [PMID: 31865831 DOI: 10.1080/10408363.2019.1700902] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Early diagnosis of cancer improves the efficacy of curative therapies. However, due to the difficulties involved in distinguishing between small early-stage tumors and normal biological variation, early detection of cancer is an extremely challenging task and there are currently no clinically validated biomarkers for a pan-cancer screening test. It is thus of particular significance that increasing evidence indicates the potential of circulating tumor DNA (ctDNA) molecules, which are fragmented segments of DNA shed from tumor cells into adjacent body fluids and the circulatory system, to serve as molecular markers for early cancer detection and thereby allow early intervention and improvement of therapeutic and survival outcomes. This is possible because ctDNA molecules bear cancer-specific fragmentation patterns, nucleosome depletion motifs, and genetic and epigenetic alterations, as distinct from plasma DNA originating from non-cancerous tissues/cells. Compared to traditional biomarkers, ctDNA analysis therefore presents the distinctive advantage of detecting tumor-specific alterations. However, based on a thorough survey of the literature, theoretical and empirical evidence suggests that current ctDNA analysis strategies, which are mainly based on DNA mutation detection, do not demonstrate the necessary diagnostic sensitivity and specificity that is required for broad clinical implementation in a screening context. Therefore, in this review we explain the biological, physiological, and analytical challenges toward the development of clinically meaningful ctDNA tests. In addition, we explore some approaches that can be implemented in order to increase the sensitivity and specificity of ctDNA assays.
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Affiliation(s)
- Abel Jacobus Bronkhorst
- Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
| | - Vida Ungerer
- Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
| | - Stefan Holdenrieder
- Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
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Akbaş M, Koyuncu FM, Artunç Ülkümen B, Taneli F, Özdemir H. Can maternal urinary and serum carbohydrate antigen 19-9 concentrations be utilized in the diagnosis of fetal hydronephrosis? J Turk Ger Gynecol Assoc 2019; 21:41-45. [PMID: 31564081 PMCID: PMC7075403 DOI: 10.4274/jtgga.galenos.2019.2019.0101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Objective: Fetal hydronephrosis (FH) is the most common fetal renal pathology encountered in daily obstetric practice. Urinary and serum carbohydrate antigen 19-9 (CA 19-9) concentrations are elevated in obstructive renal pathologies. Our aim was to assess maternal urinary and serum CA 19-9 concentrations in pregnancies with FH and compare results with controls. Material and Methods: Twenty pregnancies with severe FH, 20 pregnancies with mild-moderate FH, and 20 healthy singleton pregnancies were included in this descriptive, case-control study. The diagnosis and classification of FH was based on the anterioposterior diameter of fetal renal pelvis. Maternal urinary and serum CA 19-9 concentrations were measured and compared between groups. Results: Severe FH cases had significantly higher maternal urinary CA 19-9 concentrations compared to controls (median: 75 vs 24 U/mL; respectively; p=0.014). Concentrations of CA 19-9 did not differ between the mild-moderate FH group and control group. No statistically significant difference was found between the groups with respect to maternal serum CA 19-9 concentrations. Conclusion: Our results show that maternal urinary CA 19-9 concentration is significantly higher in pregnancies with severe FH. However, no difference was detected in serum CA 19-9 concentrations between pregnancies with severe FH, mild-moderate FH and controls. If the mechanisms of transplacental passage and maternal urinary excretion are clarified, maternal urinary CA 19-9 may be a potential marker for indicating fetal kidney damage.
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Affiliation(s)
- Murat Akbaş
- Department of Obstetrics and Gynecology, Division of Perinatology, Manisa Celal Bayar University Faculty of Medicine, Manisa, Turkey
| | - Faik Mümtaz Koyuncu
- Department of Obstetrics and Gynecology, Division of Perinatology, Manisa Celal Bayar University Faculty of Medicine, Manisa, Turkey
| | - Burcu Artunç Ülkümen
- Department of Obstetrics and Gynecology, Division of Perinatology, Manisa Celal Bayar University Faculty of Medicine, Manisa, Turkey
| | - Fatma Taneli
- Department of Medical Biochemistry, Manisa Celal Bayar University, Manisa, Turkey
| | - Habib Özdemir
- Department of Medical Biochemistry, Manisa Celal Bayar University, Manisa, Turkey
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Jia F, Liu M, Li X, Zhang F, Yue S, Liu J. Relationship between S100A4 protein expression and pre-operative serum CA19.9 levels in pancreatic carcinoma and its prognostic significance. World J Surg Oncol 2019; 17:163. [PMID: 31526392 PMCID: PMC6747733 DOI: 10.1186/s12957-019-1707-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 09/09/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Pancreatic carcinoma (PC) is one of the most lethal malignancies, and its poor prognosis is strongly associated with invasion and metastasis. CA19.9 is considered to be the most sensitive serum marker for PC in clinical practice; however, the detection of CA19.9 in PC has a certain false positive and false negative rate. The expression of the calcium-binding protein S100A4 has been reported to be associated with poor prognosis in various cancers. This study aimed to investigate the relationship between S100A4 and CA19.9 and its prognostic significance in PC. METHODS We performed immunohistochemical staining for S100A4 in formalin-fixed, paraffin-embedded blocks of 128 PC tissues. The levels of S100A4 expression and pre-operative serum CA19.9 were correlated with clinicopathological parameters. The possible correlation between S100A4 protein expression and pre-operative serum CA19.9 levels were evaluated using the chi-square test and Spearman correlation. Survival was assessed by Kaplan-Meier analysis together with a single variable or multivariate Cox analysis. RESULTS A significant positive correlation between S100A4 expression and pre-operative serum CA19.9 level was observed in PC tissues (ρ = 0.202, P = 0.022). The co-expression of both proteins correlated significantly with tumor differentiation (ρ = - 0.280, P = 0.001), TNM stage (ρ = - 0.389, P = 0.000), and lymph node metastasis (ρ = 0.254, P = 0.008). Upregulation of S100A4 was identified as a significant, independent predictor of poor overall survival (P = 0.000). Moreover, higher serum CA19.9 levels (≥ 35 U/mL) were also recognized as an independent predictor of inferior overall survival (P = 0.001). Additionally, upregulation of S100A4 and higher pre-operative serum CA19.9 levels (≥ 35 U/mL) in patients with PC contributed to a significant decrease in overall survival (P = 0.000). CONCLUSIONS The expression levels of S100A4 in PC tissues were positively correlated with pre-operative serum CA19.9 levels. S100A4 expression and pre-operative serum CA19.9 levels were significant, independent prognostic factors for the overall survival of patients with PC. S100A4 expression/pre-operative serum CA19.9 levels may prove useful as dual prognostic biomarkers for PC. Analysis of CA19.9 in combination with S100A4 can better predict the prognosis of PC.
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Affiliation(s)
- Fuxin Jia
- Department of Hepato-pancreatico-biliary Surgery, Luo Yang Central Hospital Affiliated to Zheng Zhou University, No. 288 Zhongzhou Middle Road, Luo yang, 471000, Henan Province, China.
| | - Mengmeng Liu
- Infectious Disease Prevention and Control Institute, Luo Yang Center for Disease Control and Prevention, No. 9 Zhenghe Road, Luo yang, 471000, Henan Province, China
| | - Xiao Li
- Department of Hepato-Pancreatico-Biliary Surgery, Xijing Hospital, Air Force Medical University, No.15 Changle West Road, Xi'an, 710032, Shanxi Province, China
| | - Fen Zhang
- Department of Hepato-Pancreatico-Biliary Surgery, Xijing Hospital, Air Force Medical University, No.15 Changle West Road, Xi'an, 710032, Shanxi Province, China
| | - Shuqiang Yue
- Department of Hepato-Pancreatico-Biliary Surgery, Xijing Hospital, Air Force Medical University, No.15 Changle West Road, Xi'an, 710032, Shanxi Province, China
| | - Jiangwei Liu
- Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command of the PLA, NO. 359 Youhao North Road, Urumuqi, 830000, Xinjiang Uygur Autonomous Region, China
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Alencar R, Kendler DB, Andrade F, Nava C, Bulzico D, Cordeiro de Noronha Pessoa C, Corbo R, Vaisman F. CA19-9 as a Predictor of Worse Clinical Outcome in Medullary Thyroid Carcinoma. Eur Thyroid J 2019; 8:186-191. [PMID: 31602360 PMCID: PMC6738281 DOI: 10.1159/000497201] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/22/2019] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Medullary thyroid carcinoma (MTC) is a rare disease, and its classic tumor marker is calcitonin. However, recently, very aggressive cases have been reported to also secrete carbohydrate antigen 19-9 (CA19-9), and its role as a marker of worse prognosis has been questioned. The aim of this study was to analyze the relationship between CA19-9 serum levels and MTC outcomes. METHODS We retrospectively reviewed 122 MTC patients followed in a tertiary cancer center from 1985 to 2017. Clinical-pathologic characteristics, therapeutic approaches, and outcomes were recorded and CA19-9 was collected. RESULTS Of the 122 patients included in the study, 48 had distant metastases, and at the end of follow-up 18.1% had structural persistent disease and 32.7% had progressive disease. CA19-9 was significantly higher in those who had disease progression than in those who had not (21.4 [14.3-110.9] vs. 7.27 [0.6-44.75] U/mL, p = 0.01) and was also higher in patients who died from MTC (18.4 [14.3-110.9] vs. 7.59 [0.6-67.8] U/mL, p < 0.001). Furthermore, using a ROC curve analysis, the cutoff point for CA19-9 in MTC patients was lower than that observed in pancreatic tumors. CONCLUSION CA19-9 might have a role as a prognostic factor in addition to calcitonin and carcinoembryonic antigen in metastatic MTC.
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Affiliation(s)
- Renata Alencar
- Endocrinology Service, Department of Medicine, Instituto Nacional do Cancer (INCA), Rio de Janeiro, Brazil
- Endocrinology Service, Department of Medicine, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil
| | - Daniel Barretto Kendler
- Endocrinology Service, Department of Medicine, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil
| | - Fernanda Andrade
- Endocrinology Service, Department of Medicine, Instituto Nacional do Cancer (INCA), Rio de Janeiro, Brazil
| | - Carla Nava
- Endocrinology Service, Department of Medicine, Instituto Nacional do Cancer (INCA), Rio de Janeiro, Brazil
| | - Daniel Bulzico
- Endocrinology Service, Department of Medicine, Instituto Nacional do Cancer (INCA), Rio de Janeiro, Brazil
| | | | - Rossana Corbo
- Endocrinology Service, Department of Medicine, Instituto Nacional do Cancer (INCA), Rio de Janeiro, Brazil
- Endocrinology Service, Department of Medicine, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil
| | - Fernanda Vaisman
- Endocrinology Service, Department of Medicine, Instituto Nacional do Cancer (INCA), Rio de Janeiro, Brazil
- Endocrinology Service, Department of Medicine, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil
- *Fernanda Vaisman, MD, PhD, Endocrinology Service, Department of Medicine, Instituto Nacional do Cancer, José Alencar Gomes da Silva, INCA, HC 1, Praça da Cruz Vermelha, 23, Centro, Rio de Janeiro, RJ 20231-083 (Brazil), E-Mail
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Zeng P, Li H, Chen Y, Pei H, Zhang L. Serum CA199 levels are significantly increased in patients suffering from liver, lung, and other diseases. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019; 162:253-264. [PMID: 30905455 DOI: 10.1016/bs.pmbts.2018.12.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CA199 is a sialic acid containing glycan antigen found in both glycoproteins and glycolipids, which is recognized by monoclonal antibodies generated by hybridoma technology. The increased serum CA199 levels measured by using the monoclonal antibodies have been used as diagnostic or prognostic biomarker for pancreatic cancer. Even though increased serum CA199 levels are also observed in other cancers and noncancer diseases, it is largely unknown if CA199 levels could serve as biomarkers for other diseases as well. Therefore, in our current study, serum CA199 levels from 45,645 patients with 47 clinically defined diseases and 14,783 healthy controls who attended their annual physical examination were collected and measured by the clinical laboratory in the Affiliated Hospital of Qingdao University over the past 5 years. Based on the median, mean, and -Log10p values, we found that patients with pancreatic cancer, lung fibrosis, cirrhosis, liver cancer, hepatitis, and pancreatitis had the highest media and mean serum CA199 levels with statistical significance based on the -Log10p values. Unexpectedly, patients suffering from gout and anemia had significantly low CA199 levels compared to that of the healthy controls. These results showed that serum CA199 levels are not only increased in pancreatic and other cancer patients but also either increased or decreased in noncancer diseases. The overall data indicated that the abnormal serum CA199 level might be an indicator of system malfunction rather than a cancer biomarker in general.
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Affiliation(s)
- Pengjiao Zeng
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Hui Li
- Clinical Laboratory, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yulong Chen
- Department of Gynecology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haitao Pei
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lijuan Zhang
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China.
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Munkley J. The glycosylation landscape of pancreatic cancer. Oncol Lett 2019; 17:2569-2575. [PMID: 30854032 PMCID: PMC6388511 DOI: 10.3892/ol.2019.9885] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 12/20/2018] [Indexed: 12/21/2022] Open
Abstract
Pancreatic adenocarcinoma is a lethal disease with a 5-year survival rate of <5%, the lowest of all types of cancer. The diagnosis of pancreatic cancer relies on imaging and tissue biopsy, and the only curative therapy is complete surgical resection. Pancreatic cancer has the propensity to metastasise at an early stage and the majority of patients are diagnosed when surgery is no longer an option. Hence, there is an urgent need to identify biomarkers to enable early diagnosis, and to develop new therapeutic strategies. One approach for this involves targeting cancer-associated glycans. The most widely used serological marker in pancreatic cancer is the carbohydrate antigen CA 19-9 which contains a glycan known as sialyl Lewis A (sLeA). The CA 19-9 assay is used routinely to monitor response to treatment, but concerns have been raised about its sensitivity and specificity as a diagnostic biomarker. In addition to sLeA, a wide range of alterations to other important glycans have been observed in pancreatic cancer. These include increases in the sialyl Lewis X antigen (sLex), an increase in truncated O-glycans (Tn and sTn), increased branched and fucosylated N-glycans, upregulation of specific proteoglycans and galectins, and increased O-GlcNAcylation. Growing evidence supports crucial roles for glycans in all stages of cancer progression, and it is well established that glycans regulate tumour proliferation, invasion and metastasis. The present review describes the biological significance of glycans in pancreatic cancer, and discusses the clinical value of exploiting aberrant glycosylation to improve the diagnosis and treatment of this deadly disease.
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Affiliation(s)
- Jennifer Munkley
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK
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Zhang X, Nie H, Whited J, Wang D, Li Y, Sun XL. Recent approaches for directly profiling cell surface sialoform. Glycobiology 2019; 28:910-924. [PMID: 29800278 DOI: 10.1093/glycob/cwy046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 05/09/2018] [Indexed: 12/13/2022] Open
Abstract
Sialic acids (SAs) are nine-carbon monosaccharides existing at the terminal location of glycan structures on the cell surface and secreted glycoconjugates. The expression levels and linkages of SAs on cells and tissues, collectively known as sialoform, present the hallmark of the cells and tissues of different systems and conditions. Accordingly, detecting or profiling cell surface sialoforms is very critical for understanding the function of cell surface glycans and glycoconjugates and even the molecular mechanisms of their underlying biological processes. Further, it may provide therapeutic and diagnostic applications for different diseases. In the past decades, several kinds of SA-specific binding molecules have been developed for detecting and profiling specific sialoforms of cells and tissues; the experimental materials have expanded from frozen tissue to living cells; and the analytical technologies have advanced from histochemistry to fluorescent imaging, flow cytometry and microarrays. This review summarizes the recent bioaffinity approaches for directly detecting and profiling specific SAs or sialylglycans, and their modifications of different cells and tissues.
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Affiliation(s)
- Xiaoqing Zhang
- School of Life Science and Technology, Harbin Institute of Technology, 2 Yikuang-jie, Harbin, Heilongjiang, China
| | - Huan Nie
- School of Life Science and Technology, Harbin Institute of Technology, 2 Yikuang-jie, Harbin, Heilongjiang, China
| | - Joshua Whited
- Department of Chemistry, Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, 2121 Euclid Avenue, Cleveland, OH, USA
| | - Dan Wang
- Department of Chemistry, Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, 2121 Euclid Avenue, Cleveland, OH, USA
| | - Yu Li
- School of Life Science and Technology, Harbin Institute of Technology, 2 Yikuang-jie, Harbin, Heilongjiang, China
| | - Xue-Long Sun
- Department of Chemistry, Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, 2121 Euclid Avenue, Cleveland, OH, USA
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Tasnima N, Yu H, Yan X, Li W, Xiao A, Chen X. Facile chemoenzymatic synthesis of Lewis a (Le a) antigen in gram-scale and sialyl Lewis a (sLe a) antigens containing diverse sialic acid forms. Carbohydr Res 2018; 472:115-121. [PMID: 30562693 DOI: 10.1016/j.carres.2018.12.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 01/08/2023]
Abstract
An efficient streamlined chemoenzymatic approach has been developed for gram-scale synthesis of Lewis a angtigen (LeaβProN3) and a library of sialyl Lewis a antigens (sLeaβProN3) containing different sialic acid forms. Intially, commercially available inexpensive N-acetylglucosamine (GlcNAc) was converted to its N'-glycosyl p-toluenesulfonohydrazide in one step. Followed by chemical glycosylation, GlcNAcβProN3 was synthesized using this protecting group-free method in high yield (82%). Sequential one-pot multienzyme (OPME) β1-3-galactosylation of GlcNAcβProN3 followed by OPME α1-4-fucosylation reactions produced target LeaβProN3 in gram-scale. Structurally diverse sialic acid forms was successfully introduced using a OPME sialylation reation containing a CMP-sialic acid synthetase and Pasteurella multocida α2-3-sialyltransferase 1 (PmST1) mutant PmST1 M144D with or without a sialic acid aldolase to form sLeaβProN3 containing naturally occurring or non-natural sialic acid forms in preparative scales.
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Affiliation(s)
- Nova Tasnima
- Department of Chemistry, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Hai Yu
- Department of Chemistry, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Xuebin Yan
- College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Wanqing Li
- Department of Chemistry, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - An Xiao
- Department of Chemistry, University of California, One Shields Avenue, Davis, CA, 95616, USA
| | - Xi Chen
- Department of Chemistry, University of California, One Shields Avenue, Davis, CA, 95616, USA.
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Fiala O, Hosek P, Sorejs O, Liska V, Buchler T, Poprach A, Kucera R, Topolcan O, Sedivcova M, Finek J. The Association of Baseline Serum Tumour Markers with Outcome of Patients with Metastatic Colorectal Cancer Treated with Anti-EGFR Monoclonal Antibodies in the First Line. J Cancer 2018; 9:4255-4262. [PMID: 30519327 PMCID: PMC6277611 DOI: 10.7150/jca.26217] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 07/22/2018] [Indexed: 12/13/2022] Open
Abstract
The measurement of serum tumour markers is a simple and non-invasive method for assessing the response to systemic therapies in metastatic colorectal cancer (mCRC) and estimation of prognosis. The aim of our retrospective study was to evaluate the association of baseline serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), thymidine kinase (TK) and tissue polypeptide specific antigen (TPS) with outcome of patients with mCRC treated with combination of chemotherapy and monoclonal antibodies against epidermal growth factor receptor (anti-EGFR mAbs) in the first line. In our study, the cohort included 102 patients treated with therapy based on anti-EGFR mAbs between years 2011 and 2017 at Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Czech Republic. Serum samples were collected within one month before the initiation of treatment. In multivariate Cox analysis that included serum tumour markers and clinical baseline parameters show that high baseline serum CA 19-9 was significantly associated with worse progression-free survival (HR=1.871, p=0.0330) and also overall survival (HR=3.903, p=0.0006). We have not demonstrated association of baseline levels of CEA, TK and TPS with patients' outcome. CA 19-9 is commonly used serum tumour marker which is simple and readily available and its candidate prognostic importance in the setting of anti-EGFR therapy deserves to be studied in prospective trials.
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Affiliation(s)
- Ondrej Fiala
- Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Charles University, Czech Republic.,Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Czech Republic
| | - Petr Hosek
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Czech Republic
| | - Ondrej Sorejs
- Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Charles University, Czech Republic.,Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Czech Republic
| | - Vaclav Liska
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Czech Republic.,Department of Surgery, Medical School and University Hospital in Pilsen, Charles University, Czech Republic
| | - Tomas Buchler
- Department of Oncology and First Faculty of Medicine, Charles University and Thomayer Hospital, Czech Republic
| | - Alexandr Poprach
- Department of Comprehensive Cancer Care and Faculty of Medicine, Masaryk Memorial Cancer Institute and Masaryk University, Zluty kopec 543/7, 656 53 Brno, Czech Republic
| | - Radek Kucera
- Department of Immunochemistry, Medical School and University Hospital in Pilsen, Charles University, Czech Republic
| | - Ondrej Topolcan
- Department of Immunochemistry, Medical School and University Hospital in Pilsen, Charles University, Czech Republic
| | - Monika Sedivcova
- Bioptic Laboratory, Ltd., Molecular Pathology Laboratory, Pilsen, Czech Republic
| | - Jindrich Finek
- Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Charles University, Czech Republic
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Mellby LD, Nyberg AP, Johansen JS, Wingren C, Nordestgaard BG, Bojesen SE, Mitchell BL, Sheppard BC, Sears RC, Borrebaeck CAK. Serum Biomarker Signature-Based Liquid Biopsy for Diagnosis of Early-Stage Pancreatic Cancer. J Clin Oncol 2018; 36:2887-2894. [PMID: 30106639 DOI: 10.1200/jco.2017.77.6658] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival of < 10% because of diffuse symptoms leading to late-stage diagnosis. That survival could increase significantly if localized tumors could be detected early. Therefore, we used multiparametric analysis of blood samples to obtain a novel biomarker signature of early-stage PDAC. The signature was derived from a large patient cohort, including patients with well-defined early-stage (I and II) PDAC. This biomarker signature was validated subsequently in an independent patient cohort. PATIENTS AND METHODS The biomarker signature was derived from a case-control study, using a Scandinavian cohort, consisting of 16 patients with stage I, 132 patients with stage II, 65 patients with stage III, and 230 patients with stage IV PDAC, and 888 controls. This signature was validated subsequently in an independent case-control cohort in the United States with 15 patients with stage I, 75 patients with stage II, 15 patients with stage III, and 38 patients with stage IV PDAC, and 219 controls. An antibody microarray platform was used to identify the serum biomarker signature associated with early-stage PDAC. RESULTS Using the Scandinavian case-control study, a biomarker signature was created, discriminating samples derived from patients with stage I and II from those from controls with a receiver operating characteristic area under the curve value of 0.96. This signature, consisting of 29 biomarkers, was then validated in an independent case-control study in the United States. The biomarker signature could discriminate patients with stage I and II PDAC from controls in this independent patient cohort with a receiver operating characteristic area under the curve value of 0.96. CONCLUSION This serum biomarker signature might represent a tenable approach to detecting early-stage, localized PDAC if these findings are supported by a prospective validation study.
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Affiliation(s)
- Linda D Mellby
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Andreas P Nyberg
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Julia S Johansen
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Christer Wingren
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Børge G Nordestgaard
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Stig E Bojesen
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Breeana L Mitchell
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Brett C Sheppard
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Rosalie C Sears
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Carl A K Borrebaeck
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
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48
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Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J, Anagnostou V, Fiksel J, Cristiano S, Papp E, Speir S, Reinert T, Orntoft MBW, Woodward BD, Murphy D, Parpart-Li S, Riley D, Nesselbush M, Sengamalay N, Georgiadis A, Li QK, Madsen MR, Mortensen FV, Huiskens J, Punt C, van Grieken N, Fijneman R, Meijer G, Husain H, Scharpf RB, Diaz LA, Jones S, Angiuoli S, Ørntoft T, Nielsen HJ, Andersen CL, Velculescu VE. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med 2018; 9:9/403/eaan2415. [PMID: 28814544 DOI: 10.1126/scitranslmed.aan2415] [Citation(s) in RCA: 786] [Impact Index Per Article: 112.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/13/2017] [Accepted: 07/22/2017] [Indexed: 12/12/2022]
Abstract
Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.
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Affiliation(s)
- Jillian Phallen
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Mark Sausen
- Personal Genome Diagnostics, Baltimore, MD 21224, USA
| | - Vilmos Adleff
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Alessandro Leal
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Carolyn Hruban
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - James White
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Valsamo Anagnostou
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jacob Fiksel
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Stephen Cristiano
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Eniko Papp
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Savannah Speir
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Thomas Reinert
- Department of Molecular Medicine, Aarhus University Hospital, DK-8200 Aarhus, Denmark
| | | | - Brian D Woodward
- Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Derek Murphy
- Personal Genome Diagnostics, Baltimore, MD 21224, USA
| | | | - David Riley
- Personal Genome Diagnostics, Baltimore, MD 21224, USA
| | | | | | | | - Qing Kay Li
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | | | - Frank Viborg Mortensen
- Department of Surgical Gastroenterology, Aarhus University Hospital, DK-8000 Aarhus, Denmark
| | - Joost Huiskens
- Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Cornelis Punt
- Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Nicole van Grieken
- Department of Pathology, VU University Medical Center, Amsterdam 1081 HV, Netherlands
| | - Remond Fijneman
- Department of Pathology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands
| | - Gerrit Meijer
- Department of Pathology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands
| | - Hatim Husain
- Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Robert B Scharpf
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Luis A Diaz
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Siân Jones
- Personal Genome Diagnostics, Baltimore, MD 21224, USA
| | - Sam Angiuoli
- Personal Genome Diagnostics, Baltimore, MD 21224, USA
| | - Torben Ørntoft
- Department of Molecular Medicine, Aarhus University Hospital, DK-8200 Aarhus, Denmark
| | - Hans Jørgen Nielsen
- Department of Surgical Gastroenterology 360, Hvidovre Hospital, Hvidovre, Denmark
| | | | - Victor E Velculescu
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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49
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Zhang GM, Bai SM, Zhang GM, Ma XB. Reference intervals of carbohydrate antigen 19-9 in the apparently healthy adult population. J Clin Lab Anal 2018; 32:e22380. [PMID: 29315815 DOI: 10.1002/jcla.22380] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 12/12/2017] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND To establish reference intervals of carbohydrate antigen 19-9(CA 19-9) according to the CLSI CA28-A3 guideline and to evaluate age- and gender-related variations. METHODS Serum CA 19-9 values of 10 149 healthy subjects (from 20 years old to 60 years old) were measured from location health checkups. The relationship between CA 19-9 and age was analyzed using Spearman's approach. The reference intervals of CA19-9 were established using Q2.5 and Q97.5 , and the 90% confidence intervals of upper limits were calculated. RESULTS The reference intervals of CA 19-9 were 1.98-25.12 U/mL for males (1.97-25.06 U/mL for 20-50 years old and 2.31-26.13 U/mL for 50-60 years old) and 2.36-29.29 U/mL for adult (20-60 years old) females. The upper limit of reference intervals for all individuals was 26.45 U/mL; the level of CA 19-9 is higher in females than males. Carbohydrate antigen (CA) 19-9 is significantly associated with aging in adult males(r = .0930, P < .0001), but not in females (P = .4734). CONCLUSIONS Establishing reference intervals for CA19-9 and giving age-related reference intervals of CA19-9 using a big data of healthy adult, we first discovered that CA19-9 tends to increase with age in adult males but not in females.
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Affiliation(s)
- Gao-Ming Zhang
- Department of Laboratory Medicine, Shuyang People's Hospital, Shuyang, China.,Department of Laboratory Medicine, Shuyang Affiliated Hospital of Xuzhou Medical University, Shuyang, China
| | - Shu-Mei Bai
- Department of Laboratory Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guo-Ming Zhang
- Department of Laboratory Medicine, Shuyang People's Hospital, Shuyang, China.,Department of Laboratory Medicine, Shuyang Affiliated Hospital of Xuzhou Medical University, Shuyang, China
| | - Xiao-Bo Ma
- Department of Laboratory Medicine, Shuyang People's Hospital, Shuyang, China.,Department of Laboratory Medicine, Shuyang Affiliated Hospital of Xuzhou Medical University, Shuyang, China
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50
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Özkan H, Karakaya F, Karaeren Z, Perçinel S. Persistent Elevation of CA 19-9 Levels in the Long-term Follow-up before Laryngeal Cancer. Euroasian J Hepatogastroenterol 2017; 7:92-94. [PMID: 29201783 PMCID: PMC5663785 DOI: 10.5005/jp-journals-10018-1222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 10/01/2016] [Indexed: 11/28/2022] Open
Abstract
Introduction: CA 19-9 is used as a tumor marker in colon, pancreas, biliary, and gastric cancers. Laryngeal cancer is the most common malignant epithelial tumor among head and neck cancers and has no specific tumor marker. Case report: A 66-year-old male patient had severe reflux symptoms during 5 years and had an isolated CA 19-9 elevation. Follow-up analysis revealed that he had larynx cancer and after laryngectomy, CA 19-9 levels decreased to normal range. Discussion: Currently, CA 19-9 is not a marker for malignancy. Laryngeal carcinoma has no specific tumor marker, but laryngeal squamous cell carcinoma may be manifested by elevated CA 19-9 levels. How to cite this article: Özkan H, Karakaya F, Karaeren Z, Perçinel S. Persistent Elevation of CA 19-9 Levels in the Long-term Follow-up before Laryngeal Cancer. Euroasian J Hepato-Gastroenterol 2017;7(1):92-94.
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Affiliation(s)
- Hasan Özkan
- Department of Gastroenterology, School of Medicine, Ankara University, Ankara, Turkey
| | - Fatih Karakaya
- Department of Gastroenterology, School of Medicine, Ankara University, Ankara, Turkey
| | - Zihni Karaeren
- Department of Biochemistry, School of Medicine, Ankara University, Turkey
| | - Sibel Perçinel
- Department of Pathology, School of Medicine, Ankara University, Turkey
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